ID HTRA1_HUMAN Reviewed; 480 AA. AC Q92743; D3DRE4; Q9UNS5; DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1997, sequence version 1. DT 27-MAR-2024, entry version 206. DE RecName: Full=Serine protease HTRA1; DE EC=3.4.21.-; DE AltName: Full=High-temperature requirement A serine peptidase 1; DE AltName: Full=L56; DE AltName: Full=Serine protease 11; DE Flags: Precursor; GN Name=HTRA1; Synonyms=HTRA, PRSS11; 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=Placenta; RX PubMed=8977104; DOI=10.1016/s0014-5793(96)01229-x; RA Zumbrunn J., Trueb B.; RT "Primary structure of a putative serine protease specific for IGF-binding RT proteins."; RL FEBS Lett. 398:187-192(1996). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Crowl R.M., Luk D., Milnamow M.; RT "Genomic organization and promoter characterization of the human HTRA RT (PRSS11) gene."; RL Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 144-480, PROTEIN SEQUENCE OF 33-44, FUNCTION, RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MUTAGENESIS OF SER-328. RC TISSUE=Cartilage; RX PubMed=9852107; DOI=10.1074/jbc.273.51.34406; RA Hu S.I., Carozza M., Klein M., Nantermet P., Luk D., Crowl R.M.; RT "Human HtrA, an evolutionarily conserved serine protease identified as a RT differentially expressed gene product in osteoarthritic cartilage."; RL J. Biol. Chem. 273:34406-34412(1998). RN [5] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=15208355; DOI=10.1369/jhc.3a6186.2004; RA De Luca A., De Falco M., Fedele V., Cobellis L., Mastrogiacomo A., RA Laforgia V., Tuduce I.L., Campioni M., Giraldi D., Paggi M.G., Baldi A.; RT "The serine protease HtrA1 is upregulated in the human placenta during RT pregnancy."; RL J. Histochem. Cytochem. 52:885-892(2004). RN [6] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=16377621; DOI=10.1074/jbc.m500361200; RA Grau S., Richards P.J., Kerr B., Hughes C., Caterson B., Williams A.S., RA Junker U., Jones S.A., Clausen T., Ehrmann M.; RT "The role of human HtrA1 in arthritic disease."; RL J. Biol. Chem. 281:6124-6129(2006). RN [7] RP INVOLVEMENT IN SUSCEPTIBILITY TO ARMD7. RX PubMed=17053108; DOI=10.1126/science.1133807; RA Dewan A., Liu M., Hartman S., Zhang S.S.-M., Liu D.T.L., Zhao C., RA Tam P.O.S., Chan W.M., Lam D.S.C., Snyder M., Barnstable C., Pang C.P., RA Hoh J.; RT "HTRA1 promoter polymorphism in wet age-related macular degeneration."; RL Science 314:989-992(2006). RN [8] RP INVOLVEMENT IN SUSCEPTIBILITY TO ARMD7. RX PubMed=17053109; DOI=10.1126/science.1133811; RA Yang Z., Camp N.J., Sun H., Tong Z., Gibbs D., Cameron D.J., Chen H., RA Zhao Y., Pearson E., Li X., Chien J., DeWan A., Harmon J., Bernstein P.S., RA Shridhar V., Zabriskie N.A., Hoh J., Howes K., Zhang K.; RT "A variant of the HTRA1 gene increases susceptibility to age-related RT macular degeneration."; RL Science 314:992-993(2006). RN [9] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=20671064; DOI=10.1158/1541-7786.mcr-09-0473; RA Campioni M., Severino A., Manente L., Tuduce I.L., Toldo S., Caraglia M., RA Crispi S., Ehrmann M., He X., Maguire J., De Falco M., De Luca A., RA Shridhar V., Baldi A.; RT "The serine protease HtrA1 specifically interacts and degrades the tuberous RT sclerosis complex 2 protein."; RL Mol. Cancer Res. 8:1248-1260(2010). RN [10] RP INVOLVEMENT IN CADASIL2, VARIANTS CADASIL2 ARG-121; SER-123; GLY-133; RP LEU-166; PRO-173; ARG-284; GLY-284; GLN-285; VAL-286 AND HIS-450, VARIANTS RP VAL-20 AND GLY-51, AND CHARACTERIZATION OF VARIANTS CADASIL2 ARG-121; RP LEU-166; PRO-173; ARG-284; GLY-284; GLN-285; VAL-286 AND HIS-450. RX PubMed=26063658; DOI=10.1093/brain/awv155; RA Verdura E., Herve D., Scharrer E., del Mar Amador M., Guyant-Marechal L., RA Philippi A., Corlobe A., Bergametti F., Gazal S., Prieto-Morin C., RA Beaufort N., Le Bail B., Viakhireva I., Dichgans M., Chabriat H., RA Haffner C., Tournier-Lasserve E.; RT "Heterozygous HTRA1 mutations are associated with autosomal dominant RT cerebral small vessel disease."; RL Brain 138:2347-2358(2015). RN [11] RP STRUCTURE BY NMR OF 367-480. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the PDZ-domain of human protease HTRA 1 precursor."; RL Submitted (APR-2008) to the PDB data bank. RN [12] RP X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 158-480, HOMOTRIMERIZATION, RP SUBCELLULAR LOCATION, MUTAGENESIS OF SER-328, SITE, AND ACTIVE SITE. RX PubMed=21297635; DOI=10.1038/nsmb.2013; RA Truebestein L., Tennstaedt A., Monig T., Krojer T., Canellas F., Kaiser M., RA Clausen T., Ehrmann M.; RT "Substrate-induced remodeling of the active site regulates human HTRA1 RT activity."; RL Nat. Struct. Mol. Biol. 18:386-388(2011). RN [13] RP VARIANTS CARASIL THR-252 AND MET-297, AND CHARACTERIZATION OF VARIANTS RP CARASIL THR-252 AND MET-297. RX PubMed=19387015; DOI=10.1056/nejmoa0801560; RA Hara K., Shiga A., Fukutake T., Nozaki H., Miyashita A., Yokoseki A., RA Kawata H., Koyama A., Arima K., Takahashi T., Ikeda M., Shiota H., RA Tamura M., Shimoe Y., Hirayama M., Arisato T., Yanagawa S., Tanaka A., RA Nakano I., Ikeda S., Yoshida Y., Yamamoto T., Ikeuchi T., Kuwano R., RA Nishizawa M., Tsuji S., Onodera O.; RT "Association of HTRA1 mutations and familial ischemic cerebral small-vessel RT disease."; RL N. Engl. J. Med. 360:1729-1739(2009). CC -!- FUNCTION: Serine protease with a variety of targets, including CC extracellular matrix proteins such as fibronectin. HTRA1-generated CC fibronectin fragments further induce synovial cells to up-regulate MMP1 CC and MMP3 production. May also degrade proteoglycans, such as aggrecan, CC decorin and fibromodulin. Through cleavage of proteoglycans, may CC release soluble FGF-glycosaminoglycan complexes that promote the range CC and intensity of FGF signals in the extracellular space. Regulates the CC availability of insulin-like growth factors (IGFs) by cleaving IGF- CC binding proteins. Inhibits signaling mediated by TGF-beta family CC members. This activity requires the integrity of the catalytic site, CC although it is unclear whether TGF-beta proteins are themselves CC degraded. By acting on TGF-beta signaling, may regulate many CC physiological processes, including retinal angiogenesis and neuronal CC survival and maturation during development. Intracellularly, degrades CC TSC2, leading to the activation of TSC2 downstream targets. CC {ECO:0000269|PubMed:16377621, ECO:0000269|PubMed:20671064, CC ECO:0000269|PubMed:9852107}. CC -!- SUBUNIT: Forms homotrimers. In the presence of substrate, may form CC higher-order multimers in a PDZ-independent manner. Interacts with TGF- CC beta family members, including BMP4, TGFB1, TGFB2, activin A and GDF5 CC (By similarity). {ECO:0000250}. CC -!- INTERACTION: CC Q92743; Q92743: HTRA1; NbExp=7; IntAct=EBI-352256, EBI-352256; CC Q92743; P83105: HTRA4; NbExp=5; IntAct=EBI-352256, EBI-21776319; CC Q92743; P10636-8: MAPT; NbExp=9; IntAct=EBI-352256, EBI-366233; CC Q92743; P14174: MIF; NbExp=3; IntAct=EBI-352256, EBI-372712; CC Q92743; PRO_0000035842 [P07996]: THBS1; NbExp=2; IntAct=EBI-352256, EBI-13915509; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21297635}. CC Secreted {ECO:0000269|PubMed:15208355, ECO:0000269|PubMed:9852107}. CC Cytoplasm, cytosol {ECO:0000269|PubMed:15208355, CC ECO:0000269|PubMed:20671064}. Note=Predominantly secreted CC (PubMed:15208355). Also found associated with the plasma membrane CC (PubMed:21297635). {ECO:0000269|PubMed:15208355, CC ECO:0000269|PubMed:21297635}. CC -!- TISSUE SPECIFICITY: Widely expressed, with strongest expression in CC placenta (at protein level). Secreted by synovial fibroblasts. Up- CC regulated in osteoarthritis and rheumatoid arthritis synovial fluids CC and cartilage as compared with non-arthritic (at protein level). CC {ECO:0000269|PubMed:15208355, ECO:0000269|PubMed:16377621, CC ECO:0000269|PubMed:9852107}. CC -!- DEVELOPMENTAL STAGE: In the placenta, in the first trimester of CC gestation, low expression in the cells surrounding villi both in the CC inner layer of the cytotrophoblast and in the outer layer of the CC syncytiotrophoblast (at protein level). In the third trimester of CC gestation, very strong expression in the outer layer forming the CC syncytiotrophoblast and lower in the cytotrophoblast (at protein CC level). {ECO:0000269|PubMed:15208355}. CC -!- DOMAIN: The IGFBP N-terminal domain mediates interaction with TSC2 CC substrate. CC -!- DISEASE: Macular degeneration, age-related, 7 (ARMD7) [MIM:610149]: A CC form of age-related macular degeneration, a multifactorial eye disease CC and the most common cause of irreversible vision loss in the developed CC world. In most patients, the disease is manifest as ophthalmoscopically CC visible yellowish accumulations of protein and lipid that lie beneath CC the retinal pigment epithelium and within an elastin-containing CC structure known as Bruch membrane. {ECO:0000269|PubMed:17053108, CC ECO:0000269|PubMed:17053109}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Cerebral arteriopathy, autosomal recessive, with subcortical CC infarcts and leukoencephalopathy (CARASIL) [MIM:600142]: A CC cerebrovascular disease characterized by non-hypertensive arteriopathy CC of cerebral small vessels with subcortical infarcts, alopecia, and CC spondylosis. Small cerebral arteries show arteriosclerotic changes, CC fibrous intimal proliferation, and hyaline degeneration with splitting CC of the intima and/or the internal elastic membrane. Neurologic features CC include progressive dementia, gait disturbances, extrapyramidal and CC pyramidal signs, and demyelination of the cerebral white matter with CC sparing of U fibers. {ECO:0000269|PubMed:19387015}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Cerebral arteriopathy, autosomal dominant, with subcortical CC infarcts and leukoencephalopathy, 2 (CADASIL2) [MIM:616779]: A CC cerebrovascular disease characterized by multiple subcortical infarcts, CC pseudobulbar palsy, dementia, and the presence of granular deposits in CC small cerebral arteries producing ischemic stroke. CC {ECO:0000269|PubMed:26063658}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41877/HTRA1"; 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; Y07921; CAA69226.1; -; mRNA. DR EMBL; AF157623; AAD41525.1; -; Genomic_DNA. DR EMBL; CH471066; EAW49312.1; -; Genomic_DNA. DR EMBL; CH471066; EAW49313.1; -; Genomic_DNA. DR EMBL; AF097709; AAC97211.1; -; mRNA. DR CCDS; CCDS7630.1; -. DR RefSeq; NP_002766.1; NM_002775.4. DR PDB; 2JOA; NMR; -; A=380-480. DR PDB; 2YTW; NMR; -; A=370-480. DR PDB; 3NUM; X-ray; 2.75 A; A=158-480. DR PDB; 3NWU; X-ray; 3.20 A; A/B/C=158-375. DR PDB; 3NZI; X-ray; 2.75 A; A=158-480. DR PDB; 3TJN; X-ray; 3.00 A; A/B/D=161-367. DR PDB; 3TJO; X-ray; 2.30 A; A/B/D=161-370. DR PDB; 3TJQ; X-ray; 2.00 A; A=35-156. DR PDB; 6Z0E; X-ray; 2.60 A; A/B=161-375. DR PDB; 6Z0X; X-ray; 3.10 A; A/B/C=161-375. DR PDB; 6Z0Y; X-ray; 2.20 A; A/B/C=161-375. DR PDB; 7SJN; EM; 3.40 A; A/B/C=161-367. DR PDB; 7SJO; EM; 3.30 A; A/B/C=161-379. DR PDB; 7SJP; X-ray; 2.10 A; E=190-200. DR PDBsum; 2JOA; -. DR PDBsum; 2YTW; -. DR PDBsum; 3NUM; -. DR PDBsum; 3NWU; -. DR PDBsum; 3NZI; -. DR PDBsum; 3TJN; -. DR PDBsum; 3TJO; -. DR PDBsum; 3TJQ; -. DR PDBsum; 6Z0E; -. DR PDBsum; 6Z0X; -. DR PDBsum; 6Z0Y; -. DR PDBsum; 7SJN; -. DR PDBsum; 7SJO; -. DR PDBsum; 7SJP; -. DR AlphaFoldDB; Q92743; -. DR BMRB; Q92743; -. DR EMDB; EMD-25162; -. DR EMDB; EMD-25163; -. DR SMR; Q92743; -. DR BioGRID; 111635; 42. DR DIP; DIP-33195N; -. DR IntAct; Q92743; 44. DR MINT; Q92743; -. DR STRING; 9606.ENSP00000357980; -. DR BindingDB; Q92743; -. DR ChEMBL; CHEMBL4523419; -. DR GuidetoPHARMACOLOGY; 3194; -. DR MEROPS; S01.277; -. DR iPTMnet; Q92743; -. DR PhosphoSitePlus; Q92743; -. DR BioMuta; HTRA1; -. DR DMDM; 18202620; -. DR EPD; Q92743; -. DR jPOST; Q92743; -. DR MassIVE; Q92743; -. DR PaxDb; 9606-ENSP00000357980; -. DR PeptideAtlas; Q92743; -. DR ProteomicsDB; 75437; -. DR Pumba; Q92743; -. DR Antibodypedia; 32265; 315 antibodies from 32 providers. DR DNASU; 5654; -. DR Ensembl; ENST00000368984.8; ENSP00000357980.3; ENSG00000166033.13. DR GeneID; 5654; -. DR KEGG; hsa:5654; -. DR MANE-Select; ENST00000368984.8; ENSP00000357980.3; NM_002775.5; NP_002766.1. DR UCSC; uc001lgj.2; human. DR AGR; HGNC:9476; -. DR CTD; 5654; -. DR DisGeNET; 5654; -. DR GeneCards; HTRA1; -. DR GeneReviews; HTRA1; -. DR HGNC; HGNC:9476; HTRA1. DR HPA; ENSG00000166033; Tissue enhanced (ovary). DR MalaCards; HTRA1; -. DR MIM; 600142; phenotype. DR MIM; 602194; gene. DR MIM; 610149; phenotype. DR MIM; 616779; phenotype. DR neXtProt; NX_Q92743; -. DR OpenTargets; ENSG00000166033; -. DR Orphanet; 199354; Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy. DR Orphanet; 482077; HTRA1-related autosomal dominant cerebral small vessel disease. DR Orphanet; 252128; Malignant peripheral nerve sheath tumor with perineurial differentiation. DR Orphanet; 252212; Malignant triton tumor. DR Orphanet; 279; NON RARE IN EUROPE: Age-related macular degeneration. DR PharmGKB; PA33829; -. DR VEuPathDB; HostDB:ENSG00000166033; -. DR eggNOG; KOG1320; Eukaryota. DR GeneTree; ENSGT00940000156955; -. DR HOGENOM; CLU_020120_6_2_1; -. DR InParanoid; Q92743; -. DR OrthoDB; 2159919at2759; -. DR PhylomeDB; Q92743; -. DR TreeFam; TF323480; -. DR BRENDA; 3.4.21.107; 2681. DR BRENDA; 3.4.21.108; 2681. DR PathwayCommons; Q92743; -. DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix. DR SignaLink; Q92743; -. DR BioGRID-ORCS; 5654; 16 hits in 1157 CRISPR screens. DR ChiTaRS; HTRA1; human. DR EvolutionaryTrace; Q92743; -. DR GeneWiki; HTRA1; -. DR GenomeRNAi; 5654; -. DR Pharos; Q92743; Tchem. DR PRO; PR:Q92743; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q92743; Protein. DR Bgee; ENSG00000166033; Expressed in tendon of biceps brachii and 204 other cell types or tissues. DR ExpressionAtlas; Q92743; baseline and differential. DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0019838; F:growth factor binding; IEA:UniProtKB-KW. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0140677; F:molecular function activator activity; EXP:DisProt. DR GO; GO:0004252; F:serine-type endopeptidase activity; IBA:GO_Central. DR GO; GO:0008236; F:serine-type peptidase activity; ISS:UniProtKB. DR GO; GO:0060718; P:chorionic trophoblast cell differentiation; IEA:Ensembl. DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IEA:Ensembl. DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IEA:Ensembl. DR GO; GO:0001890; P:placenta development; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0012501; P:programmed cell death; IBA:GO_Central. DR GO; GO:0006508; P:proteolysis; ISS:UniProtKB. DR CDD; cd00104; KAZAL_FS; 1. DR CDD; cd00987; PDZ_serine_protease; 1. DR Gene3D; 2.30.42.10; -; 1. DR Gene3D; 2.40.10.120; -; 1. DR Gene3D; 3.30.60.30; -; 1. DR Gene3D; 4.10.40.20; -; 1. DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf. DR InterPro; IPR000867; IGFBP-like. DR InterPro; IPR002350; Kazal_dom. DR InterPro; IPR036058; Kazal_dom_sf. DR InterPro; IPR001478; PDZ. DR InterPro; IPR041489; PDZ_6. DR InterPro; IPR036034; PDZ_sf. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR001940; Peptidase_S1C. DR PANTHER; PTHR22939; SERINE PROTEASE FAMILY S1C HTRA-RELATED; 1. DR PANTHER; PTHR22939:SF13; SERINE PROTEASE HTRA1; 1. DR Pfam; PF00219; IGFBP; 1. DR Pfam; PF07648; Kazal_2; 1. DR Pfam; PF17820; PDZ_6; 1. DR Pfam; PF13365; Trypsin_2; 1. DR PRINTS; PR00834; PROTEASES2C. DR SMART; SM00121; IB; 1. DR SMART; SM00280; KAZAL; 1. DR SMART; SM00228; PDZ; 1. DR SUPFAM; SSF57184; Growth factor receptor domain; 1. DR SUPFAM; SSF100895; Kazal-type serine protease inhibitors; 1. DR SUPFAM; SSF50156; PDZ domain-like; 1. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS51323; IGFBP_N_2; 1. DR PROSITE; PS51465; KAZAL_2; 1. DR PROSITE; PS50106; PDZ; 1. DR Genevisible; Q92743; HS. PE 1: Evidence at protein level; KW 3D-structure; Age-related macular degeneration; Cell membrane; Cytoplasm; KW Direct protein sequencing; Disease variant; Disulfide bond; KW Growth factor binding; Hydrolase; Membrane; Protease; Reference proteome; KW Secreted; Serine protease; Signal. FT SIGNAL 1..22 FT /evidence="ECO:0000255" FT CHAIN 23..480 FT /note="Serine protease HTRA1" FT /id="PRO_0000026943" FT DOMAIN 33..113 FT /note="IGFBP N-terminal" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653" FT DOMAIN 98..157 FT /note="Kazal-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DOMAIN 365..467 FT /note="PDZ" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143" FT REGION 204..364 FT /note="Serine protease" FT ACT_SITE 220 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:21297635" FT ACT_SITE 250 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:21297635" FT ACT_SITE 328 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:21297635" FT SITE 169 FT /note="Involved in trimer stabilization" FT /evidence="ECO:0000269|PubMed:21297635" FT SITE 171 FT /note="Involved in trimer stabilization" FT /evidence="ECO:0000269|PubMed:21297635" FT SITE 278 FT /note="Involved in trimer stabilization" FT /evidence="ECO:0000269|PubMed:21297635" FT DISULFID 37..62 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653" FT DISULFID 41..64 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653" FT DISULFID 46..65 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653" FT DISULFID 53..68 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653" FT DISULFID 76..89 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653" FT DISULFID 83..110 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653" FT DISULFID 112..130 FT /evidence="ECO:0000305" FT DISULFID 119..155 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT VARIANT 20 FT /note="A -> V (in dbSNP:rs369149111)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076371" FT VARIANT 51 FT /note="E -> G" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076372" FT VARIANT 121 FT /note="S -> R (in CADASIL2)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076373" FT VARIANT 123 FT /note="A -> S (in CADASIL2)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076374" FT VARIANT 133 FT /note="R -> G (in CADASIL2)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076375" FT VARIANT 166 FT /note="R -> L (in CADASIL2; loss of proteolytic activity; FT dbSNP:rs864622781)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076376" FT VARIANT 173 FT /note="A -> P (in CADASIL2; loss of proteolytic activity; FT dbSNP:rs781563777)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076377" FT VARIANT 252 FT /note="A -> T (in CARASIL; has 21 to 50% normal protease FT activity; is unable to suppress TGF-beta activity; FT dbSNP:rs113993968)" FT /evidence="ECO:0000269|PubMed:19387015" FT /id="VAR_063148" FT VARIANT 284 FT /note="S -> G (in CADASIL2; partial loss of proteolytic FT activity)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076378" FT VARIANT 284 FT /note="S -> R (in CADASIL2; loss of proteolytic activity; FT dbSNP:rs864622782)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076379" FT VARIANT 285 FT /note="P -> Q (in CADASIL2; loss of proteolytic activity)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076380" FT VARIANT 286 FT /note="F -> V (in CADASIL2; loss of proteolytic activity)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076381" FT VARIANT 297 FT /note="V -> M (in CARASIL; has 21 to 50% normal protease FT activity; is unable to suppress TGF-beta activity; FT dbSNP:rs113993969)" FT /evidence="ECO:0000269|PubMed:19387015" FT /id="VAR_063149" FT VARIANT 450 FT /note="D -> H (in CADASIL2; uncertain significance; small FT decrease, if any, in proteolytic activity; FT dbSNP:rs772225907)" FT /evidence="ECO:0000269|PubMed:26063658" FT /id="VAR_076382" FT MUTAGEN 328 FT /note="S->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:21297635, FT ECO:0000269|PubMed:9852107" FT CONFLICT 323 FT /note="I -> T (in Ref. 4; AAC97211)" FT /evidence="ECO:0000305" FT HELIX 43..45 FT /evidence="ECO:0007829|PDB:3TJQ" FT STRAND 57..59 FT /evidence="ECO:0007829|PDB:3TJQ" FT STRAND 65..68 FT /evidence="ECO:0007829|PDB:3TJQ" FT STRAND 74..77 FT /evidence="ECO:0007829|PDB:3TJQ" FT STRAND 87..90 FT /evidence="ECO:0007829|PDB:3TJQ" FT STRAND 108..113 FT /evidence="ECO:0007829|PDB:3TJQ" FT STRAND 118..123 FT /evidence="ECO:0007829|PDB:3TJQ" FT STRAND 125..128 FT /evidence="ECO:0007829|PDB:3TJQ" FT HELIX 129..141 FT /evidence="ECO:0007829|PDB:3TJQ" FT HELIX 165..168 FT /evidence="ECO:0007829|PDB:6Z0Y" FT HELIX 172..179 FT /evidence="ECO:0007829|PDB:6Z0Y" FT TURN 180..182 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 183..191 FT /evidence="ECO:0007829|PDB:6Z0Y" FT TURN 193..195 FT /evidence="ECO:0007829|PDB:7SJP" FT STRAND 198..208 FT /evidence="ECO:0007829|PDB:6Z0Y" FT TURN 211..213 FT /evidence="ECO:0007829|PDB:3NUM" FT STRAND 214..217 FT /evidence="ECO:0007829|PDB:6Z0Y" FT TURN 219..221 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 224..231 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 233..235 FT /evidence="ECO:0007829|PDB:3NZI" FT STRAND 237..246 FT /evidence="ECO:0007829|PDB:6Z0Y" FT TURN 247..250 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 251..255 FT /evidence="ECO:0007829|PDB:6Z0Y" FT HELIX 270..272 FT /evidence="ECO:0007829|PDB:3TJO" FT STRAND 278..282 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 285..288 FT /evidence="ECO:0007829|PDB:6Z0E" FT STRAND 292..297 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 301..303 FT /evidence="ECO:0007829|PDB:3TJN" FT HELIX 304..306 FT /evidence="ECO:0007829|PDB:3NZI" FT STRAND 319..321 FT /evidence="ECO:0007829|PDB:6Z0Y" FT HELIX 325..327 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 328..333 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 339..348 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 351..356 FT /evidence="ECO:0007829|PDB:6Z0Y" FT HELIX 357..369 FT /evidence="ECO:0007829|PDB:6Z0Y" FT STRAND 380..382 FT /evidence="ECO:0007829|PDB:2YTW" FT STRAND 384..389 FT /evidence="ECO:0007829|PDB:2JOA" FT HELIX 392..401 FT /evidence="ECO:0007829|PDB:2JOA" FT STRAND 411..417 FT /evidence="ECO:0007829|PDB:2JOA" FT STRAND 419..421 FT /evidence="ECO:0007829|PDB:2JOA" FT HELIX 422..426 FT /evidence="ECO:0007829|PDB:2JOA" FT STRAND 433..437 FT /evidence="ECO:0007829|PDB:2YTW" FT HELIX 445..454 FT /evidence="ECO:0007829|PDB:2JOA" FT STRAND 456..464 FT /evidence="ECO:0007829|PDB:2JOA" FT STRAND 467..473 FT /evidence="ECO:0007829|PDB:2JOA" FT STRAND 476..478 FT /evidence="ECO:0007829|PDB:2YTW" SQ SEQUENCE 480 AA; 51287 MW; CA20A99480FB2330 CRC64; MQIPRAALLP LLLLLLAAPA SAQLSRAGRS APLAAGCPDR CEPARCPPQP EHCEGGRARD ACGCCEVCGA PEGAACGLQE GPCGEGLQCV VPFGVPASAT VRRRAQAGLC VCASSEPVCG SDANTYANLC QLRAASRRSE RLHRPPVIVL QRGACGQGQE DPNSLRHKYN FIADVVEKIA PAVVHIELFR KLPFSKREVP VASGSGFIVS EDGLIVTNAH VVTNKHRVKV ELKNGATYEA KIKDVDEKAD IALIKIDHQG KLPVLLLGRS SELRPGEFVV AIGSPFSLQN TVTTGIVSTT QRGGKELGLR NSDMDYIQTD AIINYGNSGG PLVNLDGEVI GINTLKVTAG ISFAIPSDKI KKFLTESHDR QAKGKAITKK KYIGIRMMSL TSSKAKELKD RHRDFPDVIS GAYIIEVIPD TPAEAGGLKE NDVIISINGQ SVVSANDVSD VIKRESTLNM VVRRGNEDIM ITVIPEEIDP //