ID ADCY8_HUMAN Reviewed; 1251 AA. AC P40145; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1995, sequence version 1. DT 29-SEP-2021, entry version 187. DE RecName: Full=Adenylate cyclase type 8 {ECO:0000305}; DE EC=4.6.1.1 {ECO:0000250|UniProtKB:P40146}; DE AltName: Full=ATP pyrophosphate-lyase 8; DE AltName: Full=Adenylate cyclase type VIII {ECO:0000303|PubMed:8076676}; DE AltName: Full=Adenylyl cyclase 8 {ECO:0000303|PubMed:25403481}; DE Short=AC8; DE AltName: Full=Ca(2+)/calmodulin-activated adenylyl cyclase; GN Name=ADCY8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Brain stem; RX PubMed=8076676; DOI=10.1016/0014-5793(94)00836-1; RA Defer N., Marinx O., Stengel D., Danisova A., Iourgenko V., Matsuoka I., RA Caput D., Hanoune J.; RT "Molecular cloning of the human type VIII adenylyl cyclase."; RL FEBS Lett. 351:109-113(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] OF 577-1251, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=1715695; DOI=10.1016/0006-291x(91)91392-p; RA Parma J., Stengel D., Gannage M.H., Poyard M., Barouki R., Hanoune J.; RT "Sequence of a human brain adenylyl cyclase partial cDNA: evidence for a RT consensus cyclase specific domain."; RL Biochem. Biophys. Res. Commun. 179:455-462(1991). RN [3] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [4] RP TISSUE SPECIFICITY. RX PubMed=25403481; DOI=10.1007/s00125-014-3445-z; RA Raoux M., Vacher P., Papin J., Picard A., Kostrzewa E., Devin A., RA Gaitan J., Limon I., Kas M.J., Magnan C., Lang J.; RT "Multilevel control of glucose homeostasis by adenylyl cyclase 8."; RL Diabetologia 58:749-757(2015). RN [5] RP VARIANT [LARGE SCALE ANALYSIS] LEU-881. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Catalyzes the formation of cAMP in response to calcium entry CC leadings to cAMP signaling activation that affect processes suche as CC synaptic plasticity and insulin secretion. Plays a role in many brain CC functions, such as learning, memory, drug addiction, and anxiety CC modulation through regulation of synaptic plasticity by modulating CC long-term memory and long-term potentiation (LTP) through CREB CC transcription factor activity modulation. Plays a central role in CC insulin secretion by controlling glucose homeostasis through glucagon- CC like peptide 1 and glucose signaling pathway and maintains insulin CC secretion through calcium-dependent PKA activation leading to vesicle CC pool replenishment. Also, allows PTGER3 to induce potentiation of CC PTGER4-mediated PLA2 secretion by switching from a negative to a CC positive regulation, during the IL1B induced-dedifferentiation of CC smooth muscle cells. {ECO:0000250|UniProtKB:P40146}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP = 3',5'-cyclic AMP + diphosphate; Xref=Rhea:RHEA:15389, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58165; EC=4.6.1.1; CC Evidence={ECO:0000250|UniProtKB:P40146}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:P40146}; CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000250|UniProtKB:P40146}; CC Note=Binds 2 magnesium ions per subunit. Is also active with manganese CC (in vitro). {ECO:0000250|UniProtKB:P30803}; CC -!- ACTIVITY REGULATION: At rest, the N- and C-terminal domains interact, CC as part of a larger autoinhibitory complex, with calmodulin pre- CC associated at the N-terminal domain. Upon a calcium rise, calmodulin CC becomes calcium-saturated and subsequently binds to the C-terminal CC domain. Fully calcium-saturated calmodulin then leaves the N-terminal CC domain, binding solely to the C-terminal domain, and the whole CC autoinhibitory complex dissociates, resulting in activation of CC adenylate cyclase. As local calcium concentrations decrease, the CC calmodulin becomes calcium free and binds once more to the N-terminal CC domain, whereupon the whole system returns to rest with the re- CC association of the autoinhibitory complex. In non-excitable cells, CC activated by capacitative calcium entry (CCE) through store-operated CC channels, namely through interaction with ORAI1 and STIM1; membrane CC raft and caveolae localization and membrane integrity are CC indispensable. CCE-mediated adenylate cyclase activity is decreased by CC AKAP5 and AKAP7. CCE-mediated adenylate cyclase activity is up- CC regulated by AKAP9 and the mitochondrially targeted AKAP1. In excitable CC cells, activated during membrane depolarization through L-type voltage- CC gated calcium channels (VGCC), leading to calcium entry; the L-type CC alpha subunit is sufficient. Activated via stimulation of the GLP1R. CC Synergistically activated by calcium/calmodulin and GNAS. Stimulated by CC forskolin. Inhibited by PKA directly bound to AKAP5 at membrane raft. CC Inhibition by acute activation of OPRM1 and activation by chronic CC activation of OPRM1 is mediated by pertussis toxin-sensitive G(i) and CC G(o) G alpha proteins and G beta-gamma dimer. Activity is inhibited by CC G beta-gamma dimer. {ECO:0000250|UniProtKB:P40146}. CC -!- SUBUNIT: Homodimer; via transmembrane domain. Monomer. Heterodimer. CC Oligemer; via transmembrane domain. Interacts with PRKAR2A and AKAP5; CC inhibits adenylate cyclase activity through PKA phosphorylation. CC Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory CC effects of PKA on adenylate cyclase activity; interaction is dependent CC of catalytically active PPP2CA; antagonizes interaction with CC calmodulin. Interacts with AKAP5 (palmitoylated form); promotes the CC phosphorylation of ADCY8 after store-operated calcium entry (SOCE) CC stimulation at membrane raft. Interacts with ORAI1; interaction is CC calcium store depletion independent; interaction occurs in membrane CC raft; interaction increases markedly after store depletion; positively CC regulates SOCE-induced adenylate cyclase activity; contributes to the CC targeting of ADCY8 to discrete regions of the plasma membrane that are CC shielded from other calcium events. Interacts with STIM1. Interacts CC with actin; interaction is calcium independent; interaction is affected CC by calcium-calmodulin; interaction controls the distribution and CC regulation of ADCY8. Interacts with calmodulin; at rest, interacts via CC N-terminal domain; upon a calcium rise, calmodulin becomes calcium- CC saturated and subsequently binds to the C-terminal domain forming an CC autoinhibitory complex; fully calcium-saturated calmodulin leaves the CC N-terminal domain, binding solely to the C-terminal domain leading to CC dissociation of autoinhibitory complex and resulting in activation of CC adenylate cyclase; antagonizes interaction with PPP2CA; interaction is CC calcium dependent. Interacts with PPP2R5D. CC {ECO:0000250|UniProtKB:P40146}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P97490}; CC Multi-pass membrane protein {ECO:0000250|UniProtKB:P97490}. Basolateral CC cell membrane {ECO:0000250|UniProtKB:P97490}. Apical cell membrane CC {ECO:0000250|UniProtKB:P97490}. Cell junction, synapse CC {ECO:0000250|UniProtKB:P97490}. Cell projection, dendrite CC {ECO:0000250|UniProtKB:P97490}. Cell projection, axon CC {ECO:0000250|UniProtKB:P97490}. Cell junction, synapse, presynaptic CC cell membrane {ECO:0000250|UniProtKB:P97490}. Cell junction, synapse, CC postsynaptic density {ECO:0000250|UniProtKB:P97490}. Membrane raft CC {ECO:0000250|UniProtKB:P40146}. Membrane, coated pit CC {ECO:0000250|UniProtKB:P40146}. Cytoplasmic vesicle, clathrin-coated CC vesicle membrane {ECO:0000250|UniProtKB:P40146}. Membrane, caveola CC {ECO:0000250|UniProtKB:P40146}. Note=Localized to dendritic arbors (By CC similarity). Monomeric N-glycosylated species localizes in membrane CC raft. In contrast, monomeric unglycosylated forms are enriched in CC clathrin-coated pits and vesicles. Dimers are also localized outside of CC membrane rafts. Membrane raft localization and integrity is CC indispensable for CCE-stimulated adenylate cyclase activity (By CC similarity). {ECO:0000250|UniProtKB:P40146, CC ECO:0000250|UniProtKB:P97490}. CC -!- TISSUE SPECIFICITY: Detected in brain cortex (PubMed:1715695). CC Expressed in islet (PubMed:25403481). {ECO:0000269|PubMed:1715695, CC ECO:0000269|PubMed:25403481}. CC -!- DOMAIN: The protein contains two modules with six transmembrane helices CC each; both are required for catalytic activity. Isolated N-terminal or CC C-terminal guanylate cyclase domains have no catalytic activity, but CC when they are brought together, enzyme activity is restored. The active CC site is at the interface of the two domains. Both contribute substrate- CC binding residues, but the catalytic metal ions are bound exclusively CC via the N-terminal guanylate cyclase domain. The two transmembrane CC clusters are necessary and suficient for the plasma membrane targeting CC and oligomers assembly. The N-terminal and C-terminal domains interact CC at rest as part of a larger autoinhibitory complex, with calmodulin CC pre-associated at the N-terminal domain; the binding is specifically CC inhibited by fully calcium-saturated calmodulin, resulting in CC activation of AC8. {ECO:0000250|UniProtKB:P26769, CC ECO:0000250|UniProtKB:P40146}. CC -!- PTM: Phosphorylated by PKA; mediates inhibition of adenylate cyclase CC activity at membrane raft; does not influence either CALM1 or PPP2CA CC interaction with ADCY8. {ECO:0000250|UniProtKB:P40146}. CC -!- PTM: N-glycosylated; N-glycosylation is responsible for raft-targeting; CC is not necessary for CCE-stimulated adenylate cyclase activity. CC {ECO:0000250|UniProtKB:P40146}. CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Z35309; CAA84552.1; -; mRNA. DR EMBL; M83533; AAA35523.2; -; mRNA. DR CCDS; CCDS6363.1; -. DR PIR; PQ0227; PQ0227. DR PIR; S48687; S48687. DR RefSeq; NP_001106.1; NM_001115.2. DR SMR; P40145; -. DR BioGRID; 106627; 3. DR IntAct; P40145; 1. DR STRING; 9606.ENSP00000286355; -. DR BindingDB; P40145; -. DR ChEMBL; CHEMBL2960; -. DR GlyGen; P40145; 3 sites. DR iPTMnet; P40145; -. DR PhosphoSitePlus; P40145; -. DR BioMuta; ADCY8; -. DR DMDM; 729242; -. DR MassIVE; P40145; -. DR PaxDb; P40145; -. DR PeptideAtlas; P40145; -. DR PRIDE; P40145; -. DR ProteomicsDB; 55337; -. DR Antibodypedia; 4355; 229 antibodies. DR DNASU; 114; -. DR Ensembl; ENST00000286355; ENSP00000286355; ENSG00000155897. DR GeneID; 114; -. DR KEGG; hsa:114; -. DR UCSC; uc003ytd.5; human. DR CTD; 114; -. DR DisGeNET; 114; -. DR GeneCards; ADCY8; -. DR HGNC; HGNC:239; ADCY8. DR HPA; ENSG00000155897; Tissue enhanced (brain, epididymis). DR MIM; 103070; gene. DR neXtProt; NX_P40145; -. DR OpenTargets; ENSG00000155897; -. DR PharmGKB; PA29; -. DR VEuPathDB; HostDB:ENSG00000155897; -. DR eggNOG; KOG3619; Eukaryota. DR GeneTree; ENSGT00940000158742; -. DR HOGENOM; CLU_001072_3_0_1; -. DR InParanoid; P40145; -. DR OMA; TLNCLND; -. DR OrthoDB; 107368at2759; -. DR PhylomeDB; P40145; -. DR TreeFam; TF313845; -. DR PathwayCommons; P40145; -. DR Reactome; R-HSA-163359; Glucagon signaling in metabolic regulation. DR Reactome; R-HSA-163615; PKA activation. DR Reactome; R-HSA-164378; PKA activation in glucagon signalling. DR Reactome; R-HSA-170660; Adenylate cyclase activating pathway. DR Reactome; R-HSA-170670; Adenylate cyclase inhibitory pathway. DR Reactome; R-HSA-381676; Glucagon-like Peptide-1 (GLP1) regulates insulin secretion. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR Reactome; R-HSA-418597; G alpha (z) signalling events. DR Reactome; R-HSA-432040; Vasopressin regulates renal water homeostasis via Aquaporins. DR Reactome; R-HSA-442720; CREB1 phosphorylation through the activation of Adenylate Cyclase. DR Reactome; R-HSA-5610787; Hedgehog 'off' state. DR Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production. DR Reactome; R-HSA-9664323; FCGR3A-mediated IL10 synthesis. DR SIGNOR; P40145; -. DR BioGRID-ORCS; 114; 7 hits in 1009 CRISPR screens. DR ChiTaRS; ADCY8; human. DR GeneWiki; ADCY8; -. DR GenomeRNAi; 114; -. DR Pharos; P40145; Tbio. DR PRO; PR:P40145; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; P40145; protein. DR Bgee; ENSG00000155897; Expressed in spinal cord and 104 other tissues. DR ExpressionAtlas; P40145; baseline and differential. DR Genevisible; P40145; HS. DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB. DR GO; GO:0030424; C:axon; ISS:UniProtKB. DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB. DR GO; GO:0005901; C:caveola; ISS:UniProtKB. DR GO; GO:0005905; C:clathrin-coated pit; ISS:UniProtKB. DR GO; GO:0030665; C:clathrin-coated vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030425; C:dendrite; ISS:UniProtKB. DR GO; GO:0060076; C:excitatory synapse; ISS:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0098686; C:hippocampal mossy fiber to CA3 synapse; IEA:Ensembl. DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central. DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl. DR GO; GO:0016020; C:membrane; ISS:UniProtKB. DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB. DR GO; GO:0032809; C:neuronal cell body membrane; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0044853; C:plasma membrane raft; ISS:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB. DR GO; GO:0048786; C:presynaptic active zone; ISS:UniProtKB. DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; ISS:UniProtKB. DR GO; GO:0004016; F:adenylate cyclase activity; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0008294; F:calcium- and calmodulin-responsive adenylate cyclase activity; ISS:UniProtKB. DR GO; GO:0005516; F:calmodulin binding; ISS:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0046983; F:protein dimerization activity; ISS:UniProtKB. DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB. DR GO; GO:0051721; F:protein phosphatase 2A binding; ISS:UniProtKB. DR GO; GO:0034199; P:activation of protein kinase A activity; ISS:UniProtKB. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central. DR GO; GO:0006171; P:cAMP biosynthetic process; IBA:GO_Central. DR GO; GO:0071277; P:cellular response to calcium ion; ISS:UniProtKB. DR GO; GO:1904322; P:cellular response to forskolin; ISS:UniProtKB. DR GO; GO:0071377; P:cellular response to glucagon stimulus; ISS:UniProtKB. DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB. DR GO; GO:0071315; P:cellular response to morphine; ISS:UniProtKB. DR GO; GO:0038003; P:G protein-coupled opioid receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0010255; P:glucose mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro. DR GO; GO:0007611; P:learning or memory; TAS:ProtInc. DR GO; GO:0007626; P:locomotory behavior; ISS:UniProtKB. DR GO; GO:0007616; P:long-term memory; IEA:Ensembl. DR GO; GO:0007613; P:memory; ISS:UniProtKB. DR GO; GO:0150076; P:neuroinflammatory response; ISS:UniProtKB. DR GO; GO:0032793; P:positive regulation of CREB transcription factor activity; ISS:UniProtKB. DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; ISS:UniProtKB. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; ISS:UniProtKB. DR GO; GO:1900454; P:positive regulation of long-term synaptic depression; ISS:UniProtKB. DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:UniProtKB. DR GO; GO:0031915; P:positive regulation of synaptic plasticity; ISS:UniProtKB. DR GO; GO:0051259; P:protein complex oligomerization; ISS:UniProtKB. DR GO; GO:0051260; P:protein homooligomerization; ISS:UniProtKB. DR GO; GO:0080135; P:regulation of cellular response to stress; ISS:UniProtKB. DR GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; ISS:UniProtKB. DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR CDD; cd07302; CHD; 2. DR Gene3D; 3.30.70.1230; -; 2. DR InterPro; IPR001054; A/G_cyclase. DR InterPro; IPR018297; A/G_cyclase_CS. DR InterPro; IPR032628; AC_N. DR InterPro; IPR030672; Adcy. DR InterPro; IPR009398; Adcy_conserved_dom. DR InterPro; IPR029787; Nucleotide_cyclase. DR Pfam; PF16214; AC_N; 1. DR Pfam; PF06327; DUF1053; 1. DR Pfam; PF00211; Guanylate_cyc; 2. DR PIRSF; PIRSF039050; Ade_cyc; 1. DR SMART; SM00044; CYCc; 2. DR SUPFAM; SSF55073; SSF55073; 2. DR PROSITE; PS00452; GUANYLATE_CYCLASE_1; 2. DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 2. PE 1: Evidence at protein level; KW ATP-binding; cAMP biosynthesis; Cell junction; Cell membrane; KW Cell projection; Coated pit; Cytoplasmic vesicle; Glycoprotein; Lyase; KW Magnesium; Manganese; Membrane; Metal-binding; Methylation; KW Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat; Synapse; KW Transmembrane; Transmembrane helix. FT CHAIN 1..1251 FT /note="Adenylate cyclase type 8" FT /id="PRO_0000195705" FT TOPO_DOM 1..182 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 183..203 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 212..232 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 247..267 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 274..294 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 296..316 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 321..341 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 342..715 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 716..736 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 738..758 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 787..807 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 831..851 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 861..881 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 894..914 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 915..1251 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT NP_BIND 419..424 FT /note="ATP" FT /evidence="ECO:0000250|UniProtKB:P30803" FT NP_BIND 461..463 FT /note="ATP" FT /evidence="ECO:0000250|UniProtKB:P30803" FT NP_BIND 1109..1111 FT /note="ATP" FT /evidence="ECO:0000250|UniProtKB:P26769" FT NP_BIND 1116..1120 FT /note="ATP" FT /evidence="ECO:0000250|UniProtKB:P26769" FT REGION 1..182 FT /note="Involved in ORAI1, STIM1, PPP2CA and PPP2R1A FT interaction" FT /evidence="ECO:0000250|UniProtKB:P40146" FT REGION 1..109 FT /note="Involved in AKAP5 and PRKAR2A interaction" FT /evidence="ECO:0000250|UniProtKB:P40146" FT REGION 50..92 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1109..1251 FT /note="Involved in CALM1 interaction" FT /evidence="ECO:0000250|UniProtKB:P40146" FT REGION 1200..1215 FT /note="Required for both calcium stimulation and FT maintenance of autoinhibition" FT /evidence="ECO:0000250|UniProtKB:P40146" FT REGION 1223..1251 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 38..40 FT /note="Essential for CALM1 interaction" FT /evidence="ECO:0000250|UniProtKB:P40146" FT MOTIF 49..51 FT /note="Essential for CALM1 interaction" FT /evidence="ECO:0000250|UniProtKB:P40146" FT COMPBIAS 1223..1241 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT METAL 419 FT /note="Magnesium 1; catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099" FT METAL 419 FT /note="Magnesium 2; catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099" FT METAL 420 FT /note="Magnesium 2; via carbonyl oxygen; catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099" FT METAL 463 FT /note="Magnesium 1; catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099" FT METAL 463 FT /note="Magnesium 2; catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099" FT BINDING 507 FT /note="ATP" FT /evidence="ECO:0000250|UniProtKB:P30803" FT BINDING 1034 FT /note="ATP" FT /evidence="ECO:0000250|UniProtKB:P26769" FT BINDING 1156 FT /note="ATP" FT /evidence="ECO:0000250|UniProtKB:P26769" FT SITE 1199 FT /note="Essential for autoinhibition maintenance by FT promoting interaction of the N and C termini" FT /evidence="ECO:0000250|UniProtKB:P40146" FT SITE 1200 FT /note="Essential for autoinhibition maintenance" FT /evidence="ECO:0000250|UniProtKB:P40146" FT SITE 1203 FT /note="Essential for autoinhibition maintenance by FT promoting interaction of the N and C termini" FT /evidence="ECO:0000250|UniProtKB:P40146" FT SITE 1205 FT /note="Essential for CALM1 interaction" FT /evidence="ECO:0000250|UniProtKB:P40146" FT SITE 1207 FT /note="Essential for CALM1 interaction" FT /evidence="ECO:0000250|UniProtKB:P40146" FT MOD_RES 55 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:P97490" FT MOD_RES 614 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97490" FT MOD_RES 624 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97490" FT CARBOHYD 817 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 821 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 888 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 80 FT /note="A -> T (in dbSNP:rs2228949)" FT /id="VAR_029188" FT VARIANT 881 FT /note="F -> L (in a colorectal cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036328" SQ SEQUENCE 1251 AA; 140122 MW; ABF25C40493E07C3 CRC64; MELSDVRCLT GSEELYTIHP TPPAGDGRSA SRPQRLLWQT AVRHITEQRF IHGHRGGSGS GSGGSGKASD PAGGGPNHHA PQLSGDSALP LYSLGPGERA HSTCGTKVFP ERSGSGSASG SGGGGDLGFL HLDCAPSNSD FFLNGGYSYR GVIFPTLRNS FKSRDLERLY QRYFLGQRRK SEVVMNVLDV LTKLTLLVLH LSLASAPMDP LKGILLGFFT GIEVVICALV VVRKDTTSHT YLQYSGVVTW VAMTTQILAA GLGYGLLGDG IGYVLFTLFA TYSMLPLPLT WAILAGLGTS LLQVILQVVI PRLAVISINQ VVAQAVLFMC MNTAGIFISY LSDRAQRQAF LETRRCVEAR LRLETENQRQ ERLVLSVLPR FVVLEMINDM TNVEDEHLQH QFHRIYIHRY ENVSILFADV KGFTNLSTTL SAQELVRMLN ELFARFDRLA HEHHCLRIKI LGDCYYCVSG LPEPRQDHAH CCVEMGLSMI KTIRYVRSRT KHDVDMRIGI HSGSVLCGVL GLRKWQFDVW SWDVDIANKL ESGGIPGRIH ISKATLDCLN GDYNVEEGHG KERNEFLRKH NIETYLIKQP EDSLLSLPED IVKESVSSSD RRNSGATFTE GSWSPELPFD NIVGKQNTLA ALTRNSINLL PNHLAQALHV QSGPEEINKR IEHTIDLRSG DKLRREHIKP FSLMFKDSSL EHKYSQMRDE VFKSNLVCAF IVLLFITAIQ SLLPSSRVMP MTIQFSILIM LHSALVLITT AEDYKCLPLI LRKTCCWINE TYLARNVIIF ASILINFLGA ILNILWCDFD KSIPLKNLTF NSSAVFTDIC SYPEYFVFTG VLAMVTCAVF LRLNSVLKLA VLLIMIAIYA LLTETVYAGL FLRYDNLNHS GEDFLGTKEV SLLLMAMFLL AVFYHGQQLE YTARLDFLWR VQAKEEINEM KELREHNENM LRNILPSHVA RHFLEKDRDN EELYSQSYDA VGVMFASIPG FADFYSQTEM NNQGVECLRL LNEIIADFDE LLGEDRFQDI EKIKTIGSTY MAVSGLSPEK QQCEDKWGHL CALADFSLAL TESIQEINKH SFNNFELRIG ISHGSVVAGV IGAKKPQYDI WGKTVNLASR MDSTGVSGRI QVPEETYLIL KDQGFAFDYR GEIYVKGISE QEGKIKTYFL LGRVQPNPFI LPPRRLPGQY SLAAVVLGLV QSLNRQRQKQ LLNENNNTGI IKGHYNRRTL LSPSGTEPGA QAEGTDKSDL P //