ID MBTP2_HUMAN Reviewed; 519 AA. AC O43462; Q9UM70; Q9UMD3; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1998, sequence version 1. DT 27-MAR-2024, entry version 193. DE RecName: Full=Membrane-bound transcription factor site-2 protease {ECO:0000305}; DE EC=3.4.24.85 {ECO:0000269|PubMed:10805775, ECO:0000269|PubMed:11163209}; DE AltName: Full=Endopeptidase S2P {ECO:0000303|PubMed:9659902}; DE AltName: Full=Sterol regulatory element-binding proteins intramembrane protease {ECO:0000303|PubMed:9659902}; DE Short=SREBPs intramembrane protease {ECO:0000303|PubMed:9659902}; GN Name=MBTPS2 {ECO:0000303|PubMed:19361614, GN ECO:0000312|HGNC:HGNC:15455}; GN Synonyms=S2P {ECO:0000303|PubMed:16417584, GN ECO:0000303|PubMed:9659902}; 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], FUNCTION, TISSUE SPECIFICITY, AND MUTAGENESIS RP OF HIS-171; GLU-172; HIS-175 AND ASP-467. RC TISSUE=Fibroblast; RX PubMed=9659902; DOI=10.1016/s1097-2765(00)80006-4; RA Rawson R.B., Zelenski N.G., Nijhawan D., Ye J., Sakai J., Hasan M.T., RA Chang T.Y., Brown M.S., Goldstein J.L.; RT "Complementation cloning of S2P, a gene encoding a putative metalloprotease RT required for intramembrane cleavage of SREBPs."; RL Mol. Cell 1:47-57(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15772651; DOI=10.1038/nature03440; RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C., RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., RA Rogers J., Bentley D.R.; RT "The DNA sequence of the human X chromosome."; RL Nature 434:325-337(2005). RN [3] RP TOPOLOGY, AND GLYCOSYLATION AT ASN-337. RX PubMed=10419520; DOI=10.1074/jbc.274.31.21973; RA Zelenski N.G., Rawson R.B., Brown M.S., Goldstein J.L.; RT "Membrane topology of S2P, a protein required for intramembranous cleavage RT of sterol regulatory element-binding proteins."; RL J. Biol. Chem. 274:21973-21980(1999). RN [4] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=11163209; DOI=10.1016/s1097-2765(00)00133-7; RA Ye J., Rawson R.B., Komuro R., Chen X., Dave U.P., Prywes R., Brown M.S., RA Goldstein J.L.; RT "ER stress induces cleavage of membrane-bound ATF6 by the same proteases RT that process SREBPs."; RL Mol. Cell 6:1355-1364(2000). RN [5] RP FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=10805775; DOI=10.1073/pnas.97.10.5123; RA Ye J., Dave U.P., Grishin N.V., Goldstein J.L., Brown M.S.; RT "Asparagine-proline sequence within membrane-spanning segment of SREBP RT triggers intramembrane cleavage by site-2 protease."; RL Proc. Natl. Acad. Sci. U.S.A. 97:5123-5128(2000). RN [6] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=16417584; DOI=10.1111/j.1471-4159.2005.03596.x; RA Murakami T., Kondo S., Ogata M., Kanemoto S., Saito A., Wanaka A., RA Imaizumi K.; RT "Cleavage of the membrane-bound transcription factor OASIS in response to RT endoplasmic reticulum stress."; RL J. Neurochem. 96:1090-1100(2006). RN [7] RP SUBCELLULAR LOCATION, VARIANTS IFAP1 ILE-87; LEU-226; LEU-227; HIS-429 AND RP SER-475, AND CHARACTERIZATION OF VARIANTS IFAP1 ILE-87; LEU-226; LEU-227; RP HIS-429 AND SER-475. RX PubMed=19361614; DOI=10.1016/j.ajhg.2009.03.014; RA Oeffner F., Fischer G., Happle R., Konig A., Betz R.C., Bornholdt D., RA Neidel U., Boente Mdel C., Redler S., Romero-Gomez J., Salhi A., RA Vera-Casano A., Weirich C., Grzeschik K.H.; RT "IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc RT metalloprotease essential for cholesterol homeostasis and ER stress RT response."; RL Am. J. Hum. Genet. 84:459-467(2009). RN [8] RP VARIANT KFSDX SER-508, AND CHARACTERIZATION OF VARIANT KFSDX SER-508. RX PubMed=20672378; DOI=10.1002/humu.21335; RA Aten E., Brasz L.C., Bornholdt D., Hooijkaas I.B., Porteous M.E., RA Sybert V.P., Vermeer M.H., Vossen R.H., van der Wielen M.J., Bakker E., RA Breuning M.H., Grzeschik K.H., Oosterwijk J.C., den Dunnen J.T.; RT "Keratosis follicularis spinulosa decalvans is caused by mutations in RT MBTPS2."; RL Hum. Mutat. 31:1125-1133(2010). RN [9] RP INVOLVEMENT IN OLMSX, AND VARIANT OLMSX SER-464. RX PubMed=22931912; DOI=10.1038/jid.2012.289; RA Haghighi A., Scott C.A., Poon D.S., Yaghoobi R., Saleh-Gohari N., RA Plagnol V., Kelsell D.P.; RT "A missense mutation in the MBTPS2 gene underlies the X-linked form of RT Olmsted syndrome."; RL J. Invest. Dermatol. 133:571-573(2013). RN [10] RP FUNCTION, INVOLVEMENT IN OI19, VARIANTS OI19 SER-459 AND PHE-505, AND RP CHARACTERIZATION OF VARIANTS OI19 SER-459 AND PHE-505. RX PubMed=27380894; DOI=10.1038/ncomms11920; RA Lindert U., Cabral W.A., Ausavarat S., Tongkobpetch S., Ludin K., RA Barnes A.M., Yeetong P., Weis M., Krabichler B., Srichomthong C., RA Makareeva E.N., Janecke A.R., Leikin S., Roethlisberger B., Rohrbach M., RA Kennerknecht I., Eyre D.R., Suphapeetiporn K., Giunta C., Marini J.C., RA Shotelersuk V.; RT "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X- RT linked osteogenesis imperfecta."; RL Nat. Commun. 7:11920-11920(2016). CC -!- FUNCTION: Zinc metalloprotease that mediates intramembrane proteolysis CC of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2 CC (PubMed:11163209, PubMed:10805775). Catalyzes the second step in the CC proteolytic activation of the sterol regulatory element-binding CC proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2: cleaves SREBPs CC within the first transmembrane segment, thereby releasing the N- CC terminal segment with a portion of the transmembrane segment attached CC (PubMed:10805775, PubMed:27380894, PubMed:9659902). Mature N-terminal CC SREBP fragments shuttle to the nucleus and activate gene transcription CC (PubMed:10805775, PubMed:27380894, PubMed:9659902). Also mediates the CC second step in the proteolytic activation of the cyclic AMP-dependent CC transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:11163209). Involved CC in intramembrane proteolysis during bone formation (PubMed:27380894). CC In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates CC the second step of the regulated intramembrane proteolytic activation CC of the transcription factor CREB3L1, leading to the inhibition of cell- CC cycle progression (PubMed:16417584). {ECO:0000269|PubMed:10805775, CC ECO:0000269|PubMed:11163209, ECO:0000269|PubMed:16417584, CC ECO:0000269|PubMed:27380894, ECO:0000269|PubMed:9659902}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Cleaves several transcription factors that are type-2 CC transmembrane proteins within membrane-spanning domains. Known CC substrates include sterol regulatory element-binding protein (SREBP) CC -1, SREBP-2 and forms of the transcriptional activator ATF6. SREBP-2 CC is cleaved at the site 477-DRSRILL-|-CVLTFLCLSFNPLTSLLQWGGA-505. The CC residues Asn-Pro, 11 residues distal to the site of cleavage in the CC membrane-spanning domain, are important for cleavage by S2P CC endopeptidase. Replacement of either of these residues does not CC prevent cleavage, but there is no cleavage if both of these residues CC are replaced.; EC=3.4.24.85; Evidence={ECO:0000269|PubMed:10805775, CC ECO:0000269|PubMed:11163209}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:10805775}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:10805775}; CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305|PubMed:19361614}; Multi- CC pass membrane protein {ECO:0000255}. Cytoplasm CC {ECO:0000269|PubMed:19361614}. Golgi apparatus membrane CC {ECO:0000305|PubMed:16417584}; Multi-pass membrane protein CC {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Expressed in heart, brain, placenta, lung, liver, CC muscle, kidney and pancreas. {ECO:0000269|PubMed:9659902}. CC -!- DISEASE: IFAP syndrome 1, with or without Bresheck syndrome (IFAP1) CC [MIM:308205]: An X-linked syndrome characterized by a peculiar triad of CC follicular ichthyosis, total or subtotal atrichia, and photophobia of CC varying degree. Histopathologically, the epidermal granular layer is CC generally well-preserved or thickened at the infundibulum. Hair CC follicles are poorly developed and tend to be surrounded by an CC inflammatory infiltrate. A subgroup of patients is described with CC lamellar rather than follicular ichthyosis. Non-consistent features may CC include growth and psychomotor retardation, aganglionic megacolon, CC seizures and nail dystrophy. {ECO:0000269|PubMed:19361614}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Olmsted syndrome, X-linked (OLMSX) [MIM:300918]: A rare CC congenital disorder characterized by bilateral mutilating palmoplantar CC keratoderma and periorificial keratotic plaques with severe itching at CC all lesions. Diffuse alopecia, constriction of digits, and CC onychodystrophy have also been reported. Infections and squamous cell CC carcinomas can arise on the keratotic areas. The digital constriction CC may progress to autoamputation of fingers and toes. CC {ECO:0000269|PubMed:22931912}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Keratosis follicularis spinulosa decalvans X-linked (KFSDX) CC [MIM:308800]: A rare disorder affecting the skin and the eye. Affected CC men show thickening of the skin of the neck, ears, and extremities, CC especially the palms and soles, loss of eyebrows, eyelashes and beard, CC thickening of the eyelids with blepharitis and ectropion, and corneal CC degeneration. {ECO:0000269|PubMed:20672378}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- DISEASE: Osteogenesis imperfecta 19 (OI19) [MIM:301014]: An X-linked CC form of osteogenesis imperfecta, a connective tissue disorder CC characterized by low bone mass, bone fragility and susceptibility to CC fractures after minimal trauma. Disease severity ranges from very mild CC forms without fractures to intrauterine fractures and perinatal CC lethality. Extraskeletal manifestations, which affect a variable number CC of patients, are dentinogenesis imperfecta, hearing loss, and blue CC sclerae. OI19 is characterized by prenatal fractures, short stature, CC white sclerae, variable scoliosis and pectal deformity, striking tibial CC anterior angulation and generalized osteopenia. CC {ECO:0000269|PubMed:27380894}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase M50A family. {ECO:0000305}. 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; AF019612; AAC51937.1; -; mRNA. DR EMBL; U73479; AAD08632.1; -; Genomic_DNA. DR EMBL; U72788; AAD08631.1; -; Genomic_DNA. DR CCDS; CCDS14201.1; -. DR RefSeq; NP_056968.1; NM_015884.3. DR AlphaFoldDB; O43462; -. DR BioGRID; 119495; 70. DR IntAct; O43462; 2. DR STRING; 9606.ENSP00000368798; -. DR MEROPS; M50.001; -. DR GlyCosmos; O43462; 1 site, No reported glycans. DR GlyGen; O43462; 2 sites. DR iPTMnet; O43462; -. DR PhosphoSitePlus; O43462; -. DR BioMuta; MBTPS2; -. DR EPD; O43462; -. DR jPOST; O43462; -. DR MassIVE; O43462; -. DR MaxQB; O43462; -. DR PaxDb; 9606-ENSP00000368798; -. DR PeptideAtlas; O43462; -. DR ProteomicsDB; 48956; -. DR Antibodypedia; 483; 169 antibodies from 29 providers. DR DNASU; 51360; -. DR Ensembl; ENST00000379484.10; ENSP00000368798.5; ENSG00000012174.12. DR GeneID; 51360; -. DR KEGG; hsa:51360; -. DR MANE-Select; ENST00000379484.10; ENSP00000368798.5; NM_015884.4; NP_056968.1. DR UCSC; uc004dae.4; human. DR AGR; HGNC:15455; -. DR CTD; 51360; -. DR DisGeNET; 51360; -. DR GeneCards; MBTPS2; -. DR HGNC; HGNC:15455; MBTPS2. DR HPA; ENSG00000012174; Low tissue specificity. DR MalaCards; MBTPS2; -. DR MIM; 300294; gene. DR MIM; 300918; phenotype. DR MIM; 301014; phenotype. DR MIM; 308205; phenotype. DR MIM; 308800; phenotype. DR neXtProt; NX_O43462; -. DR OpenTargets; ENSG00000012174; -. DR Orphanet; 85284; BRESEK syndrome. DR Orphanet; 2273; Ichthyosis follicularis-alopecia-photophobia syndrome. DR Orphanet; 2340; Keratosis follicularis spinulosa decalvans. DR Orphanet; 659; Mutilating palmoplantar keratoderma with periorificial keratotic plaques. DR Orphanet; 216796; Osteogenesis imperfecta type 1. DR PharmGKB; PA30672; -. DR VEuPathDB; HostDB:ENSG00000012174; -. DR eggNOG; KOG2921; Eukaryota. DR GeneTree; ENSGT00510000048066; -. DR HOGENOM; CLU_032523_1_0_1; -. DR InParanoid; O43462; -. DR OMA; FYSWGRW; -. DR OrthoDB; 5181at2759; -. DR PhylomeDB; O43462; -. DR TreeFam; TF314478; -. DR BRENDA; 3.4.24.85; 2681. DR PathwayCommons; O43462; -. DR Reactome; R-HSA-1655829; Regulation of cholesterol biosynthesis by SREBP (SREBF). DR Reactome; R-HSA-381033; ATF6 (ATF6-alpha) activates chaperones. DR Reactome; R-HSA-8874177; ATF6B (ATF6-beta) activates chaperones. DR Reactome; R-HSA-8874211; CREB3 factors activate genes. DR Reactome; R-HSA-8963889; Assembly of active LPL and LIPC lipase complexes. DR SignaLink; O43462; -. DR SIGNOR; O43462; -. DR BioGRID-ORCS; 51360; 217 hits in 802 CRISPR screens. DR ChiTaRS; MBTPS2; human. DR GenomeRNAi; 51360; -. DR Pharos; O43462; Tbio. DR PRO; PR:O43462; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; O43462; Protein. DR Bgee; ENSG00000012174; Expressed in endothelial cell and 185 other cell types or tissues. DR ExpressionAtlas; O43462; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; ISS:UniProt. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProt. DR GO; GO:0140537; F:transcription regulator activator activity; IGI:ParkinsonsUK-UCL. DR GO; GO:0036500; P:ATF6-mediated unfolded protein response; TAS:ParkinsonsUK-UCL. DR GO; GO:0070977; P:bone maturation; IMP:UniProtKB. DR GO; GO:0008203; P:cholesterol metabolic process; TAS:ProtInc. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; TAS:Reactome. DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; IGI:ParkinsonsUK-UCL. DR GO; GO:0007095; P:mitotic G2 DNA damage checkpoint signaling; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IGI:ParkinsonsUK-UCL. DR GO; GO:0051604; P:protein maturation; IDA:UniProt. DR GO; GO:0045540; P:regulation of cholesterol biosynthetic process; TAS:Reactome. DR GO; GO:1905897; P:regulation of response to endoplasmic reticulum stress; IBA:GO_Central. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IGI:ParkinsonsUK-UCL. DR CDD; cd06162; S2P-M50_PDZ_SREBP; 1. DR Gene3D; 2.30.42.10; -; 1. DR InterPro; IPR001193; MBTPS2. DR InterPro; IPR036034; PDZ_sf. DR InterPro; IPR008915; Peptidase_M50. DR PANTHER; PTHR13325:SF3; MEMBRANE-BOUND TRANSCRIPTION FACTOR SITE-2 PROTEASE; 1. DR PANTHER; PTHR13325; PROTEASE M50 MEMBRANE-BOUND TRANSCRIPTION FACTOR SITE 2 PROTEASE; 1. DR Pfam; PF02163; Peptidase_M50; 1. DR PRINTS; PR01000; SREBPS2PTASE. DR SUPFAM; SSF50156; PDZ domain-like; 1. DR PROSITE; PS00142; ZINC_PROTEASE; 1. DR Genevisible; O43462; HS. PE 1: Evidence at protein level; KW Cholesterol metabolism; Cytoplasm; Disease variant; Glycoprotein; KW Golgi apparatus; Hydrolase; Ichthyosis; Lipid metabolism; Membrane; KW Metal-binding; Metalloprotease; Osteogenesis imperfecta; KW Palmoplantar keratoderma; Protease; Reference proteome; Steroid metabolism; KW Sterol metabolism; Transmembrane; Transmembrane helix; Zinc. FT CHAIN 1..519 FT /note="Membrane-bound transcription factor site-2 protease" FT /id="PRO_0000088482" FT TOPO_DOM 1..3 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:10419520" FT TRANSMEM 4..24 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 25..74 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:10419520" FT TRANSMEM 75..95 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 96..107 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 108..144 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:10419520" FT TRANSMEM 145..169 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 174..186 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 187..209 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 229..251 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 252..446 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:10419520" FT TRANSMEM 447..464 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 465..476 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 477..492 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 493..513 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 514..519 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 115..135 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 172 FT BINDING 171 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT BINDING 175 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT CARBOHYD 337 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:10419520" FT VARIANT 87 FT /note="M -> I (in IFAP1; does not affect subcellular FT localization; impairs activity; dbSNP:rs122468177)" FT /evidence="ECO:0000269|PubMed:19361614" FT /id="VAR_063054" FT VARIANT 226 FT /note="W -> L (in IFAP1; does not affect subcellular FT localization; impairs activity; dbSNP:rs122468180)" FT /evidence="ECO:0000269|PubMed:19361614" FT /id="VAR_063055" FT VARIANT 227 FT /note="H -> L (in IFAP1; does not affect subcellular FT localization; impairs activity; dbSNP:rs122468176)" FT /evidence="ECO:0000269|PubMed:19361614" FT /id="VAR_063056" FT VARIANT 429 FT /note="R -> H (in IFAP1; does not affect subcellular FT localization; impairs activity; dbSNP:rs122468178)" FT /evidence="ECO:0000269|PubMed:19361614" FT /id="VAR_063057" FT VARIANT 459 FT /note="N -> S (in OI19; decreased regulated intramembrane FT proteolysis resulting in reduced transcriptional activation FT of genes relevant to osteoblast differentiation and bone FT formation; dbSNP:rs1555986267)" FT /evidence="ECO:0000269|PubMed:27380894" FT /id="VAR_081103" FT VARIANT 464 FT /note="F -> S (in OLMSX; dbSNP:rs587777306)" FT /evidence="ECO:0000269|PubMed:22931912" FT /id="VAR_071323" FT VARIANT 475 FT /note="F -> S (in IFAP1; does not affect subcellular FT localization; impairs activity; dbSNP:rs122468179)" FT /evidence="ECO:0000269|PubMed:19361614" FT /id="VAR_063058" FT VARIANT 505 FT /note="L -> F (in OI19; decreased regulated intramembrane FT proteolysis resulting in reduced transcriptional activation FT of genes relevant to osteoblast differentiation and bone FT formation; dbSNP:rs1555986287)" FT /evidence="ECO:0000269|PubMed:27380894" FT /id="VAR_081104" FT VARIANT 508 FT /note="N -> S (in KFSDX; sterol responsiveness is reduced FT by half; dbSNP:rs587776867)" FT /evidence="ECO:0000269|PubMed:20672378" FT /id="VAR_064409" FT MUTAGEN 171 FT /note="H->F: Loss of activity." FT /evidence="ECO:0000269|PubMed:9659902" FT MUTAGEN 172 FT /note="E->A,Q: Loss of activity." FT /evidence="ECO:0000269|PubMed:9659902" FT MUTAGEN 172 FT /note="E->D: Partial loss of activity." FT /evidence="ECO:0000269|PubMed:9659902" FT MUTAGEN 175 FT /note="H->F: Loss of activity." FT /evidence="ECO:0000269|PubMed:9659902" FT MUTAGEN 467 FT /note="D->N: Loss of activity." FT /evidence="ECO:0000269|PubMed:9659902" SQ SEQUENCE 519 AA; 57444 MW; 247D69E0FD7747BD CRC64; MIPVSLVVVV VGGWTVVYLT DLVLKSSVYF KHSYEDWLEN NGLSISPFHI RWQTAVFNRA FYSWGRRKAR MLYQWFNFGM VFGVIAMFSS FFLLGKTLMQ TLAQMMADSP SSYSSSSSSS SSSSSSSSSS SSSSSSLHNE QVLQVVVPGI NLPVNQLTYF FTAVLISGVV HEIGHGIAAI REQVRFNGFG IFLFIIYPGA FVDLFTTHLQ LISPVQQLRI FCAGIWHNFV LALLGILALV LLPVILLPFY YTGVGVLITE VAEDSPAIGP RGLFVGDLVT HLQDCPVTNV QDWNECLDTI AYEPQIGYCI SASTLQQLSF PVRAYKRLDG STECCNNHSL TDVCFSYRNN FNKRLHTCLP ARKAVEATQV CRTNKDCKKS SSSSFCIIPS LETHTRLIKV KHPPQIDMLY VGHPLHLHYT VSITSFIPRF NFLSIDLPVV VETFVKYLIS LSGALAIVNA VPCFALDGQW ILNSFLDATL TSVIGDNDVK DLIGFFILLG GSVLLAANVT LGLWMVTAR //