MBTP2_HUMAN
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 03-AUG-2022, entry version 184.
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, ECO:0000312|HGNC:HGNC:15455};
GN Synonyms=S2P {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 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 [7]
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 [8]
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 [9]
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 {ECO:0000269|PubMed:10805775, ECO:0000269|PubMed:11163209,
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:0000305|PubMed:19361614}. Cytoplasm
CC {ECO:0000269|PubMed:19361614}.
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}.
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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; 64.
DR IntAct; O43462; 2.
DR STRING; 9606.ENSP00000368798; -.
DR MEROPS; M50.001; -.
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; O43462; -.
DR PeptideAtlas; O43462; -.
DR PRIDE; O43462; -.
DR ProteomicsDB; 48956; -.
DR Antibodypedia; 483; 150 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 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; CMHYPYD; -.
DR OrthoDB; 1012405at2759; -.
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-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; 194 hits in 711 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 183 other tissues.
DR ExpressionAtlas; O43462; baseline and differential.
DR Genevisible; O43462; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004222; F:metalloendopeptidase activity; EXP:Reactome.
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:0051091; P:positive regulation of DNA-binding transcription factor activity; IGI:ParkinsonsUK-UCL.
DR GO; GO:1990440; P:positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress; IGI:ParkinsonsUK-UCL.
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; ISS:ParkinsonsUK-UCL.
DR Gene3D; 2.30.42.10; -; 1.
DR InterPro; IPR001193; MBTPS2.
DR InterPro; IPR036034; PDZ_sf.
DR InterPro; IPR008915; Peptidase_M50.
DR PANTHER; PTHR13325; PTHR13325; 1.
DR Pfam; PF02163; Peptidase_M50; 1.
DR PRINTS; PR01000; SREBPS2PTASE.
DR SUPFAM; SSF50156; SSF50156; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW Cholesterol metabolism; Cytoplasm; Disease variant; Glycoprotein;
KW Hydrolase; Ichthyosis; Lipid metabolism; Membrane; Metal-binding;
KW Metalloprotease; Osteogenesis imperfecta; Palmoplantar keratoderma;
KW Protease; Reference proteome; Steroid metabolism; Sterol metabolism;
KW 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
