{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P05067","secondaryAccessions":["B2R5V1","B4DII8","D3DSD1","D3DSD2","D3DSD3","P09000","P78438","Q13764","Q13778","Q13793","Q16011","Q16014","Q16019","Q16020","Q6GSC0","Q8WZ99","Q9BT38","Q9UC33","Q9UCA9","Q9UCB6","Q9UCC8","Q9UCD1","Q9UQ58"],"uniProtkbId":"A4_HUMAN","entryAudit":{"firstPublicDate":"1987-08-13","lastAnnotationUpdateDate":"2026-01-28","lastSequenceUpdateDate":"1991-11-01","entryVersion":318,"sequenceVersion":3},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:620"}],"value":"Amyloid-beta 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Interaction between APP molecules on neighboring cells promotes synaptogenesis (PubMed:25122912). Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (PubMed:17062754, PubMed:23011729). Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1"}],"commentType":"FUNCTION"},{"texts":[{"value":"Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Amyloid-beta peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Also binds GPC1 in lipid rafts"}],"commentType":"FUNCTION"},{"texts":[{"value":"More effective reductant than amyloid-beta protein 40. May activate mononuclear phagocytes in the brain and elicit inflammatory responses"}],"commentType":"FUNCTION","molecule":"Amyloid-beta protein 42"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain"}],"commentType":"FUNCTION"},{"texts":[{"value":"The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10081969"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10681545"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10816430"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11238726"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11278849"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11438549"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11517218"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11544248"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11689470"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11724784"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11877420"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11943163"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14527950"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15347684"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16174740"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16407538"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17051221"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17855360"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17895381"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18468999"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19366692"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19901339"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20212142"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20811458"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22457725"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23011729"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24336208"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24523320"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25122912"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25168729"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28720718"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30630874"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8446172"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8626687"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8855266"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8887653"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9300481"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9338779"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9843960"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9890987"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and, NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons. Interacts with CPEB1 and AGER (By similarity). Interacts with ANKS1B. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE (PubMed:17051221). Homodimerizes; dimerization is enhanced in the presence of Cu(2+) ions and is promoted by heparin binding (PubMed:25122912, PubMed:20212142). Interacts with PLD3. Interacts with VDAC1 (PubMed:25168729). Interacts with NSG1; could regulate APP processing (By similarity). Interacts with SYT7 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30630874). Interacts with LRRK2 (PubMed:28720718). Interacts (via cytoplasmic domain) with KIF5B (PubMed:23011729). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (PubMed:14527950, PubMed:8855266). Interacts (via intracellular domain) with APBB3 (PubMed:10081969). Amyloid-beta associates with HADH2 (PubMed:9338779). Soluble APP binds, via its N-terminal head, to FBLN1"}],"commentType":"SUBUNIT"},{"texts":[{"value":"Interacts with S100A9"}],"commentType":"SUBUNIT","molecule":"Amyloid-beta protein 40"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11689470"}],"value":"Interacts with FPR2"}],"commentType":"SUBUNIT","molecule":"Amyloid-beta protein 42"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20811458"}],"value":"Interacts with GSAP"}],"commentType":"SUBUNIT","molecule":"C83"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16174740"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16407538"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17855360"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24523320"}],"value":"Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta 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Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles (PubMed:20580937). During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body (PubMed:10341243). Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10383380"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20580937"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2649245"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"25122912"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30630874"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"10383380"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"25122912"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2900137"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"22584060"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2900137"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30630874"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"22584060"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10341243"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10341243"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20580937"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20580937"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20580937"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25122912"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C83","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14527950"}],"value":"Endoplasmic reticulum","id":"SL-0095"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14527950"}],"value":"Golgi apparatus","id":"SL-0132"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14527950"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C99","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14527950"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10656250"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2649245"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 40","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16154999"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11689470"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11689470"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16154999"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11544248"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65) (PubMed:11544248). In dopaminergic neurons, the phosphorylated Thr-743 form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11544248"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11544248"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"APP770"},"synonyms":[{"value":"PreA4 770"}],"isoformIds":["P05067-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"APP305"},"isoformIds":["P05067-2"],"sequenceIds":["VSP_000005","VSP_000006"],"isoformSequenceStatus":"Described"},{"name":{"value":"L-APP677"},"isoformIds":["P05067-3"],"sequenceIds":["VSP_000002","VSP_000004","VSP_000009"],"isoformSequenceStatus":"Described"},{"name":{"value":"APP695"},"synonyms":[{"value":"PreA4 695"}],"isoformIds":["P05067-4"],"sequenceIds":["VSP_000002","VSP_000004"],"isoformSequenceStatus":"Described"},{"name":{"value":"L-APP696"},"isoformIds":["P05067-5"],"sequenceIds":["VSP_000002","VSP_000003","VSP_000009"],"isoformSequenceStatus":"Described"},{"name":{"value":"APP714"},"isoformIds":["P05067-6"],"sequenceIds":["VSP_000002","VSP_000003"],"isoformSequenceStatus":"Described"},{"name":{"value":"L-APP733"},"isoformIds":["P05067-7"],"sequenceIds":["VSP_000007","VSP_000008","VSP_000009"],"isoformSequenceStatus":"Described"},{"name":{"value":"APP751"},"synonyms":[{"value":"PreA4 751"}],"isoformIds":["P05067-8"],"sequenceIds":["VSP_000007","VSP_000008"],"isoformSequenceStatus":"Described"},{"name":{"value":"L-APP752"},"isoformIds":["P05067-9"],"sequenceIds":["VSP_000009"],"isoformSequenceStatus":"Described"},{"name":{"value":"APP639"},"isoformIds":["P05067-10"],"sequenceIds":["VSP_009116","VSP_009117","VSP_009118"],"isoformSequenceStatus":"Described"},{"name":{"value":"11"},"isoformIds":["P05067-11"],"sequenceIds":["VSP_045446","VSP_045447"],"isoformSequenceStatus":"Described"}],"note":{"texts":[{"value":"Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12859342"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1406936"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2649245"}],"value":"Expressed in the brain and in cerebrospinal fluid (at protein level) (PubMed:2649245). Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex-opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra-striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non-neuronal cells. Isoform APP751 is the most abundant form in T-lymphocytes. Appican is expressed in astrocytes"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"value":"Increased levels during neuronal differentiation"}],"commentType":"INDUCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30630874"}],"value":"The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9843960"}],"value":"The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25122912"}],"value":"The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10383380"}],"value":"The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26898943"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28570778"}],"value":"The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2649245"}],"value":"The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10656250"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11604391"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16154999"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30630874"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro) (PubMed:30630874). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE (PubMed:11604391, PubMed:16154999). Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase and all terminating at Gln-686"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10319819"}],"value":"Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either CASP6, CASP8 or CASP9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16335952"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21712440"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22576872"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2649245"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2900137"}],"value":"N-glycosylated (PubMed:2900137). N- and O-glycosylated (PubMed:2649245). O-glycosylation on Ser and Thr residues with core 1 or possibly core 8 glycans. Partial tyrosine glycosylation (Tyr-681) is found on some minor, short amyloid-beta peptides (amyloid-beta 1-15, 1-16, 1-17, 1-18, 1-19 and 1-20) but not found on amyloid-beta protein 38, amyloid-beta protein 40 nor on amyloid-beta protein 42. Modification on a tyrosine is unusual and is more prevelant in AD patients. Glycans had Neu5AcHex(Neu5Ac)HexNAc-O-Tyr, Neu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr and O-AcNeu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr structures, where O-Ac is O-acetylation of Neu5Ac. Neu5AcNeu5Ac is most likely Neu5Ac 2,8Neu5Ac linked. O-glycosylations in the vicinity of the cleavage sites may influence the proteolytic processing. Appicans are L-APP isoforms with O-linked chondroitin sulfate"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10341243"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11146006"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11517218"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11877420"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28720718"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8131745"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8999878"}],"value":"Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific (PubMed:10341243). Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins (PubMed:10341243). Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta (PubMed:11146006, PubMed:8131745). The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members (PubMed:11517218). In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis (PubMed:28720718). Phosphorylation on Tyr-757 is required for SHC binding (PubMed:11877420). Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin (PubMed:8999878)"}],"commentType":"PTM"},{"texts":[{"value":"Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond. In vitro, the APP-Cu(+) complex in the presence of hydrogen peroxide results in an increased production of amyloid-beta-containing peptides"}],"commentType":"PTM"},{"texts":[{"value":"Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Amyloid-beta peptides are degraded by IDE"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2649245"}],"value":"Sulfated on tyrosine residues"}],"commentType":"PTM"},{"commentType":"MASS SPECTROMETRY","molecule":"Gamma-secretase C-terminal fragment 59","method":"MALDI","molWeight":6461.6,"molWeightError":0.0,"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12214090"}]},{"commentType":"MASS SPECTROMETRY","molecule":"Gamma-secretase C-terminal fragment 57","method":"MALDI","molWeight":6451.6,"molWeightError":0.0,"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12214090"}]},{"commentType":"DISEASE","disease":{"diseaseId":"Alzheimer disease 1","diseaseAccession":"DI-00085","acronym":"AD1","description":"A form of Alzheimer disease, a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. It can be associated with cerebral amyloid angiopathy. Alzheimer disease can be associated with cerebral amyloid angiopathy.","diseaseCrossReference":{"database":"MIM","id":"104300"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10097173"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10631141"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10656250"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10665499"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10677483"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10867787"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11063718"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11311152"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11528419"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12034808"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1302033"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1303239"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1303275"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1415269"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1465129"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15201367"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15365148"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15668448"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1671712"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1678058"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1908231"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1925564"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1944558"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8267572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8290042"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8476439"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8577393"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8886002"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9328472"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9754958"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Cerebral amyloid angiopathy, APP-related","diseaseAccession":"DI-00097","acronym":"CAA-APP","description":"A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.","diseaseCrossReference":{"database":"MIM","id":"605714"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11409420"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12654973"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16178030"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20697050"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2111584"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26898943"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28570778"}],"value":"Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. The affinity for copper is much higher than for other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding"}],"commentType":"MISCELLANEOUS"},{"texts":[{"value":"A major isoform"}],"commentType":"MISCELLANEOUS","molecule":"Isoform APP770"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"The L-isoforms are referred to as appicans"}],"commentType":"MISCELLANEOUS","molecule":"Isoform L-APP677"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"A major isoform"}],"commentType":"MISCELLANEOUS","molecule":"Isoform APP695"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"The L-isoforms are referred to as appicans"}],"commentType":"MISCELLANEOUS","molecule":"Isoform L-APP696"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"The L-isoforms are referred to as appicans"}],"commentType":"MISCELLANEOUS","molecule":"Isoform L-APP733"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"A major isoform"}],"commentType":"MISCELLANEOUS","molecule":"Isoform APP751"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU01217"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"19225519"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"38110576"}],"value":"Was reported to bind TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6) (PubMed:19225519). This work was later retracted (PubMed:38110576)"}],"commentType":"CAUTION"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Miscellaneous discrepancy","sequence":"AAA58727.1","note":"Contamination by an Alu repeat.","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"WEB RESOURCE","resourceName":"Alzforum","resourceUrl":"https://www.alzforum.org/mutations/app","ftp":false,"note":"APP mutations"},{"commentType":"WEB RESOURCE","resourceName":"AD mutations","resourceUrl":"https://uantwerpen.vib.be/CMTMutations","ftp":false},{"commentType":"WEB RESOURCE","resourceName":"Wikipedia","resourceUrl":"https://en.wikipedia.org/wiki/Amyloid_beta","ftp":false,"note":"Amyloid beta entry"}],"features":[{"type":"Signal","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":17,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12665801"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2900137"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"3597385"}]},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":770,"modifier":"EXACT"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000000088"},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":687,"modifier":"EXACT"}},"description":"Soluble APP-alpha","featureId":"PRO_0000000089"},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":671,"modifier":"EXACT"}},"description":"Soluble 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP. Inhibits G(o)-alpha ATPase activity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse amyloid-beta peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Amyloid-beta protein 42 may activate mononuclear phagocytes in the brain and elicits inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also binds GPC1 in lipid rafts (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"value":"Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23011729"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons (By similarity). Amyloid-beta associates with HADH2 (By similarity). Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). Isoform APP695 interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). The C99 fragment also interacts with SORL1 (By similarity). Isoform APP751 interacts with SORL1 (By similarity). Isoform APP770 interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts with SYT7 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (PubMed:23011729). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10341243"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. APP sorts to the basolateral surface in epithelial cells (By similarity). During neuronal differentiation, the Thr-742 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body (PubMed:10341243). Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10341243"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10341243"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C83","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Endoplasmic reticulum","id":"SL-0095"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Golgi apparatus","id":"SL-0132"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C99","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65) (By similarity). In dopaminergic neurons, the phosphorylated Thr-743 form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"value":"Nucleus","id":"SL-0191"}},{"location":{"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"APP770"},"isoformIds":["P08592-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"APP695"},"isoformIds":["P08592-2"],"sequenceIds":["VSP_000015","VSP_000016"],"isoformSequenceStatus":"Described"},{"name":{"value":"L-APP677"},"isoformIds":["P08592-3"],"isoformSequenceStatus":"Not described"},{"name":{"value":"L-APP696"},"isoformIds":["P08592-4"],"isoformSequenceStatus":"Not described"},{"name":{"value":"APP714"},"isoformIds":["P08592-5"],"isoformSequenceStatus":"Not described"},{"name":{"value":"L-APP733"},"isoformIds":["P08592-6"],"isoformSequenceStatus":"Not described"},{"name":{"value":"APP751"},"isoformIds":["P08592-7"],"isoformSequenceStatus":"Not described"},{"name":{"value":"L-APP752"},"isoformIds":["P08592-8"],"isoformSequenceStatus":"Not described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23011729"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7744833"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8996834"}],"value":"Expressed in the brain (PubMed:23011729). In the brain, non-L-APP isoforms are expressed in neurons, isoform APP695 being the predominant form. In astrocytes and microglial cells, almost 50% is L-isoform (appican)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"value":"From 6 days to 7 months, levels of KPI-containing isoforms increase in the brain cortex and hippocampus. Levels of L-APP increase in all brain regions during the same period, but levels are low compared to non-L-APP isoforms"}],"commentType":"DEVELOPMENTAL STAGE"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10341243"}],"value":"Phosphorylation of mature, glycosylated APP occurs 48-72 hours after treatment of neuronal cells with nerve growth factor which correlates with the timing of neurite outgrowth"}],"commentType":"INDUCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"N-glycosylated"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11479316"}],"value":"O-glycosylated. O-linkage of chondroitin sulfate to the L-APP isoforms produces the APP proteoglycan core proteins, the appicans. The chondroitin sulfate chain of appicans contains 4-O-sulfated galactose in the linkage region and chondroitin sulfate E in the repeated disaccharide region"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10329382"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10341243"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10936190"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9085254"}],"value":"Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific (PubMed:10329382, PubMed:10341243, PubMed:9085254). Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins (PubMed:10341243). Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta (PubMed:10936190). The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members (By similarity). In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis (By similarity). Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP (By similarity). This phosphorylation is inhibited by heparin (By similarity)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Amyloid-beta peptides are degraded by IDE"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Sulfated on tyrosine residues"}],"commentType":"PTM"},{"commentType":"MASS SPECTROMETRY","molecule":"Gamma-secretase C-terminal fragment 50","method":"MALDI","molWeight":5911.3,"molWeightError":0.0,"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11483588"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000305"}],"value":"Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. 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surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP. Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons (By similarity). Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse amyloid-beta peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Amyloid-beta protein 42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also binds GPC1 in lipid rafts (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15677459"}],"value":"The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16174740"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16407538"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18650440"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21084623"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25168729"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28720718"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30429473"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1, NUMB and DAB1. Binding to DAB1 inhibits its serine phosphorylation. Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1 (By similarity). In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1 (By similarity). Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons (By similarity). Amyloid-beta associates with HADH2 (By similarity). Interacts with ANKS1B and AGER (By similarity). Interacts with CPEB1. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). Isoform APP695 interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (PubMed:16174740, PubMed:16407538). The C99 fragment also interacts with SORL1 (PubMed:16407538). Isoform APP751 interacts with SORL1 (PubMed:16174740). Isoform APP770 interacts with SORL1 (PubMed:16174740). Interacts with PLD3 (By similarity). Interacts with VDAC1 (PubMed:25168729). Interacts with NSG1; could regulate APP processing (PubMed:21084623). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts with SYT7 (PubMed:30429473). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). Interacts with LRRK2 (PubMed:28720718). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (PubMed:18650440). Interacts (via intracellular domain) with APBB3 (By 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Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment (By similarity). Associates with GPC1 in perinuclear compartments (PubMed:15677459). Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions (By similarity). Upon neuronal activation, routed into BACE1-positive recycling endosomes via a clathrin -dependent mechanism (PubMed:23931995)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26260791"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25592972"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26260791"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23931995"}],"value":"Golgi apparatus, trans-Golgi network","id":"SL-0266"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C99","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C83","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Endoplasmic reticulum","id":"SL-0095"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Golgi apparatus","id":"SL-0132"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28720718"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65) (By similarity). In dopaminergic neurons, the phosphorylated Thr-743 form is localized to the nucleus (PubMed:28720718)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28720718"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"APP770"},"isoformIds":["P12023-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"APP695"},"isoformIds":["P12023-2"],"sequenceIds":["VSP_000012","VSP_000013"],"isoformSequenceStatus":"Described"},{"name":{"value":"APP751"},"isoformIds":["P12023-3"],"sequenceIds":["VSP_000014"],"isoformSequenceStatus":"Described"},{"name":{"value":"APP714"},"isoformIds":["P12023-4"],"isoformSequenceStatus":"Not described"}],"note":{"texts":[{"value":"Additional isoforms seem to exist."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25757569"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26260791"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28720718"}],"value":"Expressed in the brain with expression in cortex, cerebellum, hippocampus, olfactory bulb, neurons, astrocytes and microglia (at protein level) (PubMed:25757569, PubMed:26260791, PubMed:28720718). Expressed in the retinal lens (PubMed:25757569). Expressed at a low level in muscle cells (at protein level) (PubMed:25757569)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8510506"}],"value":"Expressed in kidney"}],"commentType":"TISSUE SPECIFICITY","molecule":"Isoform APP770"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8510506"}],"value":"Widely expressed (PubMed:8510506). Expressed in several different brain regions including hippocampus, substantia nigra pars compacta and cerebellum (PubMed:8510506). Within the cerebellum, abundantly expressed in Purkinje cells (PubMed:8510506)"}],"commentType":"TISSUE SPECIFICITY","molecule":"Isoform APP751"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8510506"}],"value":"Expressed in the brain, kidney and liver (PubMed:8510506). Expressed in several different brain regions including hippocampus, substantia nigra pars compacta and cerebellum (PubMed:8510506). Within the cerebellum, abundantly expressed in Purkinje cells (PubMed:8510506)"}],"commentType":"TISSUE SPECIFICITY","molecule":"Isoform APP695"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8510506"}],"value":"Expressed in several different brain regions including hippocampus, substantia nigra pars compacta and cerebellum (PubMed:8510506). Within the cerebellum, abundantly expressed in Purkinje cells (PubMed:8510506)"}],"commentType":"TISSUE SPECIFICITY","molecule":"Isoform APP714"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26260791"}],"value":"Expressed in 4 to 24 week old mice"}],"commentType":"DEVELOPMENTAL STAGE"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26260791"}],"value":"Up-regulated in animals on a high-fat diet compared to a regular diet"}],"commentType":"INDUCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11553691"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23931995"}],"value":"Proteolytically processed under normal cellular conditions (PubMed:11553691, PubMed:23931995). Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99 (PubMed:11553691, PubMed:23931995). Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase (By similarity)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either CASP6, CASP8 or CASP9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"N- and O-glycosylated"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28720718"}],"value":"Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific (By similarity). Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins (By similarity). Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta (By similarity). The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members (By similarity). In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis (PubMed:28720718). Phosphorylation on Tyr-757 is required for SHC binding (By similarity). Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP (By similarity). This phosphorylation is inhibited by heparin (By similarity)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12634421"}],"value":"Amyloid-beta peptides are degraded by IDE"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Sulfated on tyrosine residues"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000305"}],"value":"Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. Rat and mouse amyloid-beta peptides have an arginine residue substituted for the bridging histidine residue and are thus less capable of forming amyloid aggregates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding (By similarity)"}],"commentType":"MISCELLANEOUS"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU01217"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Signal","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":17,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}]},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":770,"modifier":"EXACT"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000000114"},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":687,"modifier":"EXACT"}},"description":"Soluble 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. 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It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":58,"modifier":"OUTSIDE"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000226242"},{"type":"Chain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":5,"modifier":"EXACT"}},"description":"Soluble 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":58,"modifier":"OUTSIDE"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000226241"},{"type":"Chain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":6,"modifier":"EXACT"}},"description":"Soluble 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(Swiss-Prot)","primaryAccession":"Q29149","uniProtkbId":"A4_URSMA","entryAudit":{"firstPublicDate":"1997-11-01","lastAnnotationUpdateDate":"2024-11-27","lastSequenceUpdateDate":"1997-11-01","entryVersion":106,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Ursus maritimus","commonName":"Polar bear","synonyms":["Thalarctos maritimus"],"taxonId":29073,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Laurasiatheria","Carnivora","Caniformia","Ursidae","Ursus"]},"proteinExistence":"2: Evidence at transcript level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Amyloid-beta precursor protein"}},"alternativeNames":[{"fullName":{"value":"ABPP"},"shortNames":[{"value":"APP"}]},{"fullName":{"value":"Alzheimer disease amyloid A4 protein homolog"}},{"fullName":{"value":"Alzheimer disease amyloid 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Interacts with CPEB1, ANKS1B, TNFRSF21 and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. 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It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":57,"modifier":"OUTSIDE"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000226244"},{"type":"Chain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":5,"modifier":"EXACT"}},"description":"Soluble 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(Swiss-Prot)","primaryAccession":"Q28757","uniProtkbId":"A4_SHEEP","entryAudit":{"firstPublicDate":"1997-11-01","lastAnnotationUpdateDate":"2026-01-28","lastSequenceUpdateDate":"1997-11-01","entryVersion":111,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Ovis aries","commonName":"Sheep","taxonId":9940,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Laurasiatheria","Artiodactyla","Ruminantia","Pecora","Bovidae","Caprinae","Ovis"]},"proteinExistence":"2: Evidence at transcript level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Amyloid-beta precursor protein"}},"alternativeNames":[{"fullName":{"value":"ABPP"},"shortNames":[{"value":"APP"}]},{"fullName":{"value":"Alzheimer disease amyloid A4 protein homolog"}},{"fullName":{"value":"Alzheimer disease amyloid 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. 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growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons (By similarity). Amyloid-beta associates with HADH2 (By similarity). Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). The C99 fragment also interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C83","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Endoplasmic reticulum","id":"SL-0095"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Golgi apparatus","id":"SL-0132"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C99","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated Thr-743 form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"N- and O-glycosylated"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific. Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins. Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members. In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis. Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Amyloid-beta peptides are degraded by IDE"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Sulfated on tyrosine residues"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding"}],"commentType":"MISCELLANEOUS"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU01217"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Signal","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":17,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}]},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":770,"modifier":"EXACT"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000000140"},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":687,"modifier":"EXACT"}},"description":"Soluble 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to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons (By similarity). Amyloid-beta associates with HADH2 (By similarity). Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). The C99 fragment also interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C83","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Endoplasmic reticulum","id":"SL-0095"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Golgi apparatus","id":"SL-0132"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C99","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated Thr-743 form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"N- and O-glycosylated"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific. Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins. Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members. In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis. Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Amyloid-beta peptides are degraded by IDE"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Sulfated on tyrosine residues"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding"}],"commentType":"MISCELLANEOUS"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU01217"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Signal","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":17,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}]},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":770,"modifier":"EXACT"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000000127"},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":687,"modifier":"EXACT"}},"description":"Soluble 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heparin-binding domain"},{"key":"MatchStatus","value":"1"}]},{"database":"SUPFAM","id":"SSF89811","properties":[{"key":"EntryName","value":"Amyloid beta a4 protein copper binding domain (domain 2)"},{"key":"MatchStatus","value":"1"}]},{"database":"SUPFAM","id":"SSF57362","properties":[{"key":"EntryName","value":"BPTI-like"},{"key":"MatchStatus","value":"1"}]},{"database":"SUPFAM","id":"SSF109843","properties":[{"key":"EntryName","value":"CAPPD, an extracellular domain of amyloid beta A4 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LOCATION":6,"DOMAIN":6,"PTM":7,"MISCELLANEOUS":1,"SIMILARITY":1},"countByFeatureType":{"Signal":1,"Chain":13,"Peptide":2,"Topological domain":2,"Transmembrane":1,"Domain":3,"Region":10,"Motif":3,"Compositional bias":3,"Binding site":15,"Site":14,"Modified residue":11,"Glycosylation":2,"Disulfide bond":9,"Cross-link":1},"uniParcId":"UPI000036C68A"}},{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q60495","secondaryAccessions":["Q60496"],"uniProtkbId":"A4_CAVPO","entryAudit":{"firstPublicDate":"2003-04-23","lastAnnotationUpdateDate":"2026-01-28","lastSequenceUpdateDate":"2003-04-23","entryVersion":179,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Cavia porcellus","commonName":"Guinea pig","taxonId":10141,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Glires","Rodentia","Hystricomorpha","Caviidae","Cavia"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Amyloid-beta precursor protein"}},"alternativeNames":[{"fullName":{"value":"ABPP"},"shortNames":[{"value":"APP"}]},{"fullName":{"value":"Alzheimer disease amyloid A4 protein homolog"}},{"fullName":{"value":"Alzheimer disease amyloid protein"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Amyloid precursor protein"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"}],"value":"Amyloid-beta (A4) precursor protein"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"}],"value":"Amyloid-beta A4 protein"}}],"contains":[{"recommendedName":{"fullName":{"value":"N-APP"}}},{"recommendedName":{"fullName":{"value":"Soluble APP-alpha"},"shortNames":[{"value":"S-APP-alpha"}]}},{"recommendedName":{"fullName":{"value":"Soluble APP-beta"},"shortNames":[{"value":"S-APP-beta"}]}},{"recommendedName":{"fullName":{"value":"C99"}},"alternativeNames":[{"fullName":{"value":"Beta-secretase C-terminal fragment"},"shortNames":[{"value":"Beta-CTF"}]},{"fullName":{"value":"CTF-beta"}}]},{"recommendedName":{"fullName":{"value":"Amyloid-beta protein 42"},"shortNames":[{"value":"Abeta42"}]},"alternativeNames":[{"fullName":{"value":"Beta-APP42"}}]},{"recommendedName":{"fullName":{"value":"Amyloid-beta protein 40"},"shortNames":[{"value":"Abeta40"}]},"alternativeNames":[{"fullName":{"value":"Beta-APP40"}}]},{"recommendedName":{"fullName":{"value":"C83"}},"alternativeNames":[{"fullName":{"value":"Alpha-secretase C-terminal fragment"},"shortNames":[{"value":"Alpha-CTF"}]},{"fullName":{"value":"CTF-alpha"}}]},{"recommendedName":{"fullName":{"value":"P3(42)"}}},{"recommendedName":{"fullName":{"value":"P3(40)"}}},{"recommendedName":{"fullName":{"value":"C80"}}},{"recommendedName":{"fullName":{"value":"Gamma-secretase C-terminal fragment 59"}},"alternativeNames":[{"fullName":{"value":"Gamma-CTF(59)"}}]},{"recommendedName":{"fullName":{"value":"Gamma-secretase C-terminal fragment 57"}},"alternativeNames":[{"fullName":{"value":"Gamma-CTF(57)"}}]},{"recommendedName":{"fullName":{"value":"Gamma-secretase C-terminal fragment 50"}},"alternativeNames":[{"fullName":{"value":"Amyloid intracellular domain 50"},"shortNames":[{"value":"AICD-50"},{"value":"AID(50)"}]},{"fullName":{"value":"Gamma-CTF(50)"}}]},{"recommendedName":{"fullName":{"value":"C31"}}}],"flag":"Precursor"},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"APP"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"A4"},{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"AD1"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Amyloid-beta peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Also bind GPC1 in lipid rafts (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9349544"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons (By similarity). Amyloid-beta associates with HADH2 (By similarity). Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). Isoform APP695 interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Isoform APP770 interacts with SORL1 (By similarity). The C99 fragment also interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C83","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Endoplasmic reticulum","id":"SL-0095"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Golgi apparatus","id":"SL-0132"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C99","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65) (By similarity). In dopaminergic neurons, the phosphorylated Thr-743 form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"APP770"},"isoformIds":["Q60495-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"APP695"},"isoformIds":["Q60495-2"],"sequenceIds":["VSP_007221","VSP_007222"],"isoformSequenceStatus":"Described"}],"note":{"texts":[{"value":"Additional isoforms, missing exons 7,8 and 15, seem to exist. The L-isoforms, missing exon 15, are referred to as appicans."}]}},{"texts":[{"value":"Isoform APP695 is the major isoform found in brain. The longer isoforms containing the BPTI domain are predominantly expressed in peripheral organs such as muscle and liver"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"value":"Increased levels during neuronal differentiation"}],"commentType":"INDUCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10619481"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11035007"}],"value":"Proteolytically processed under normal cellular conditions (PubMed:10619481, PubMed:11035007). Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99 (PubMed:10619481, PubMed:11035007). Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase (By similarity)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically cleaved by caspases during neuronal apoptosis. 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons (By similarity). Amyloid-beta associates with HADH2 (By similarity). Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). Isoform APP695 interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Isoform APP770 interacts with SORL1 (By similarity). The C99 fragment also interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C83","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Endoplasmic reticulum","id":"SL-0095"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Golgi apparatus","id":"SL-0132"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C99","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated Thr-724 form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"APP770"},"isoformIds":["Q95241-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"APP695"},"isoformIds":["Q95241-2"],"isoformSequenceStatus":"Not described"}],"note":{"texts":[{"value":"Additional isoforms seem to exist."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-720 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"N- and O-glycosylated"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific. Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins. Phosphorylated on Thr-724 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta. The Thr-724 phosphorylated form causes a conformational change which reduces binding of Fe65 family members. In dopaminergic (DA) neurons, phosphorylation on Thr-724 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis. Phosphorylation on Tyr-738 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Amyloid-beta peptides are degraded by IDE"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Sulfated on tyrosine residues"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding"}],"commentType":"MISCELLANEOUS"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU01217"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Signal","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":17,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}]},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":751,"modifier":"EXACT"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000000172"},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":668,"modifier":"EXACT"}},"description":"Soluble 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P08592"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons (By similarity). Amyloid-beta associates with HADH2 (By similarity). Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). Isoform APP695 interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Isoform APP770 interacts with SORL1 (By similarity). The C99 fragment also interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C83","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Endoplasmic reticulum","id":"SL-0095"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Golgi apparatus","id":"SL-0132"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"C99","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated Thr-743 form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"APP770"},"isoformIds":["P53601-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"APP695"},"isoformIds":["P53601-2"],"sequenceIds":["VSP_000010","VSP_000011"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["P53601-3"],"sequenceIds":["VSP_013360","VSP_013361"],"isoformSequenceStatus":"Described"}],"note":{"texts":[{"value":"Additional isoforms seem to exist."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"N- and O-glycosylated"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific. Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins. Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members. In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis. Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"}],"value":"Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Amyloid-beta peptides are degraded by IDE"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Sulfated on tyrosine residues"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding"}],"commentType":"MISCELLANEOUS"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU01217"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Signal","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":17,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}]},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":770,"modifier":"EXACT"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000000101"},{"type":"Chain","location":{"start":{"value":18,"modifier":"EXACT"},"end":{"value":687,"modifier":"EXACT"}},"description":"Soluble 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane","id":"SL-0162"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Single-pass type I membrane protein","id":"SL-9905"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Perikaryon","id":"SL-0197"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell projection, growth cone","id":"SL-0288"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Membrane, clathrin-coated pit","id":"SL-0069"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Early endosome","id":"SL-0094"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasmic vesicle","id":"SL-0088"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Soluble APP-beta","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Secreted","id":"SL-0243"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Amyloid-beta protein 42","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Associates with FPR2 at the cell surface and the complex is then rapidly internalized"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface","id":"SL-0310"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Gamma-secretase C-terminal fragment 59","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). In dopaminergic neurons, the phosphorylated form is localized to the nucleus (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":6,"modifier":"EXACT"}},"description":"Soluble APP-beta","evidences":[{"evidenceCode":"ECO:0000250"}],"featureId":"PRO_0000000064"},{"type":"Chain","location":{"start":{"value":7,"modifier":"EXACT"},"end":{"value":59,"modifier":"OUTSIDE"}},"description":"CTF-alpha","evidences":[{"evidenceCode":"ECO:0000250"}],"featureId":"PRO_0000000065"},{"type":"Chain","location":{"start":{"value":7,"modifier":"EXACT"},"end":{"value":48,"modifier":"EXACT"}},"description":"Amyloid-beta protein 42","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"featureId":"PRO_0000000066"},{"type":"Chain","location":{"start":{"value":7,"modifier":"EXACT"},"end":{"value":46,"modifier":"EXACT"}},"description":"Amyloid-beta protein 40","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"featureId":"PRO_0000000067"},{"type":"Chain","location":{"start":{"value":47,"modifier":"EXACT"},"end":{"value":59,"modifier":"OUTSIDE"}},"description":"Gamma-secretase C-terminal fragment 59","evidences":[{"evidenceCode":"ECO:0000250"}],"featureId":"PRO_0000000068"},{"type":"Chain","location":{"start":{"value":49,"modifier":"EXACT"},"end":{"value":59,"modifier":"OUTSIDE"}},"description":"Gamma-secretase C-terminal fragment 57","evidences":[{"evidenceCode":"ECO:0000250"}],"featureId":"PRO_0000000069"},{"type":"Topological domain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":34,"modifier":"EXACT"}},"description":"Extracellular","evidences":[{"evidenceCode":"ECO:0000255"}]},{"type":"Transmembrane","location":{"start":{"value":35,"modifier":"EXACT"},"end":{"value":58,"modifier":"EXACT"}},"description":"Helical","evidences":[{"evidenceCode":"ECO:0000255"}]},{"type":"Topological domain","location":{"start":{"value":59,"modifier":"EXACT"},"end":{"value":59,"modifier":"OUTSIDE"}},"description":"Cytoplasmic","evidences":[{"evidenceCode":"ECO:0000255"}]},{"type":"Site","location":{"start":{"value":13,"modifier":"EXACT"},"end":{"value":14,"modifier":"EXACT"}},"description":"Cleavage; by ACE","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}]},{"type":"Non-terminal residue","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":1,"modifier":"EXACT"}},"description":""},{"type":"Non-terminal residue","location":{"start":{"value":59,"modifier":"EXACT"},"end":{"value":59,"modifier":"EXACT"}},"description":""}],"keywords":[{"id":"KW-0034","category":"Cellular component","name":"Amyloid"},{"id":"KW-1003","category":"Cellular component","name":"Cell membrane"},{"id":"KW-0966","category":"Cellular component","name":"Cell projection"},{"id":"KW-0168","category":"Cellular component","name":"Coated pit"},{"id":"KW-0963","category":"Cellular component","name":"Cytoplasm"},{"id":"KW-0968","category":"Cellular component","name":"Cytoplasmic vesicle"},{"id":"KW-0967","category":"Cellular component","name":"Endosome"},{"id":"KW-0472","category":"Cellular component","name":"Membrane"},{"id":"KW-0539","category":"Cellular component","name":"Nucleus"},{"id":"KW-1185","category":"Technical term","name":"Reference proteome"},{"id":"KW-0964","category":"Cellular component","name":"Secreted"},{"id":"KW-0812","category":"Domain","name":"Transmembrane"},{"id":"KW-1133","category":"Domain","name":"Transmembrane helix"}],"references":[{"referenceNumber":1,"citation":{"id":"1656157","citationType":"journal article","authors":["Johnstone E.M.","Chaney M.O.","Norris F.H.","Pascual R.","Little S.P."],"citationCrossReferences":[{"database":"PubMed","id":"1656157"},{"database":"DOI","id":"10.1016/0169-328x(91)90088-f"}],"title":"Conservation of the sequence of the Alzheimer's disease amyloid peptide in dog, polar bear and five other mammals by cross-species polymerase chain reaction analysis.","publicationDate":"1991","journal":"Brain Res. 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Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP (By similarity). Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction (By similarity). In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation (By similarity). Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P12023"}],"value":"Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Interacts with CPEB1, ANKS1B and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}],"value":"Cell surface protein that rapidly becomes internalized via clathrin-coated pits. Only a minor proportion is present at the cell membrane; most of the protein is present in intracellular vesicles. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. 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Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase"}],"commentType":"PTM"},{"commentType":"MASS SPECTROMETRY","molecule":"Amyloid-beta protein 40","method":"MALDI","molWeight":4341.336,"molWeightError":0.2,"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22576872"}]},{"commentType":"MASS SPECTROMETRY","molecule":"Amyloid-beta protein 40","method":"Electrospray","molWeight":4341.1616,"molWeightError":0.0025,"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22576872"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255"}],"value":"Belongs to the APP family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"OUTSIDE"},"end":{"value":40,"modifier":"OUTSIDE"}},"description":"Amyloid-beta precursor protein","featureId":"PRO_0000419960"},{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":40,"modifier":"EXACT"}},"description":"Amyloid-beta protein 40","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22576872"}],"featureId":"PRO_0000419961"},{"type":"Site","location":{"start":{"value":7,"modifier":"EXACT"},"end":{"value":8,"modifier":"EXACT"}},"description":"Cleavage; by ACE","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P05067"}]},{"type":"Non-terminal residue","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":1,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"22576872"}]},{"type":"Non-terminal residue","location":{"start":{"value":40,"modifier":"EXACT"},"end":{"value":40,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"22576872"}]}],"keywords":[{"id":"KW-0034","category":"Cellular component","name":"Amyloid"},{"id":"KW-1003","category":"Cellular component","name":"Cell membrane"},{"id":"KW-0966","category":"Cellular component","name":"Cell projection"},{"id":"KW-0168","category":"Cellular component","name":"Coated pit"},{"id":"KW-0968","category":"Cellular component","name":"Cytoplasmic vesicle"},{"id":"KW-0903","category":"Technical term","name":"Direct protein sequencing"},{"id":"KW-0967","category":"Cellular component","name":"Endosome"},{"id":"KW-0472","category":"Cellular component","name":"Membrane"},{"id":"KW-1185","category":"Technical term","name":"Reference proteome"}],"references":[{"referenceNumber":1,"citation":{"id":"22576872","citationType":"journal article","authors":["Brinkmalm G.","Portelius E.","Ohrfelt A.","Mattsson N.","Persson R.","Gustavsson M.K.","Vite C.H.","Gobom J.","Mansson J.E.","Nilsson J.","Halim A.","Larson G.","Ruetschi U.","Zetterberg H.","Blennow K.","Brinkmalm A."],"citationCrossReferences":[{"database":"PubMed","id":"22576872"},{"database":"DOI","id":"10.1002/jms.2987"}],"title":"An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid beta and amyloid precursor protein in human and cat cerebrospinal fluid.","publicationDate":"2012","journal":"J. 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