ID MBTP1_HUMAN Reviewed; 1052 AA. AC Q14703; A8K6V8; Q24JQ2; Q9UF67; DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 209. DE RecName: Full=Membrane-bound transcription factor site-1 protease {ECO:0000305}; DE EC=3.4.21.112 {ECO:0000269|PubMed:10644685, ECO:0000269|PubMed:21719679, ECO:0000269|PubMed:34349020}; DE AltName: Full=Endopeptidase S1P {ECO:0000303|PubMed:10944850}; DE AltName: Full=Subtilisin/kexin-isozyme 1 {ECO:0000303|PubMed:10644685}; DE Short=SKI-1 {ECO:0000303|PubMed:10644685}; DE Flags: Precursor; GN Name=MBTPS1 {ECO:0000312|HGNC:HGNC:15456}; GN Synonyms=KIAA0091 {ECO:0000303|PubMed:7788527}, S1P GN {ECO:0000303|PubMed:10944850, ECO:0000303|PubMed:16417584}, SKI1 GN {ECO:0000303|PubMed:10644685}; 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 [GENOMIC DNA], TISSUE SPECIFICITY, AND INDUCTION. RC TISSUE=Myeloid; RX PubMed=10944850; DOI=10.1007/s100380070029; RA Nakajima T., Iwaki K., Kodama T., Inazawa J., Emi M.; RT "Genomic structure and chromosomal mapping of the human site-1 protease RT (S1P) gene."; RL J. Hum. Genet. 45:212-217(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Bone marrow; RX PubMed=7788527; DOI=10.1093/dnares/2.1.37; RA Nagase T., Miyajima N., Tanaka A., Sazuka T., Seki N., Sato S., Tabata S., RA Ishikawa K., Kawarabayasi Y., Kotani H., Nomura N.; RT "Prediction of the coding sequences of unidentified human genes. III. The RT coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of RT cDNA clones from human cell line KG-1."; RL DNA Res. 2:37-43(1995). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M., RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., RA Myers R.M., Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 735-1052. RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVITY RP REGULATION, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=10644685; DOI=10.1074/jbc.275.4.2349; RA Toure B.B., Munzer J.S., Basak A., Benjannet S., Rochemont J., Lazure C., RA Chretien M., Seidah N.G.; RT "Biosynthesis and enzymatic characterization of human SKI-1/S1P and the RT processing of its inhibitory prosegment."; RL J. Biol. Chem. 275:2349-2358(2000). RN [8] RP SUBCELLULAR LOCATION. RX PubMed=9990022; DOI=10.1073/pnas.96.4.1321; RA Seidah N.G., Mowla S.J., Hamelin J., Mamarbachi A.M., Benjannet S., RA Toure B.B., Basak A., Munzer J.S., Marcinkiewicz J., Zhong M., RA Barale J.-C., Lazure C., Murphy R.A., Chretien M., Marcinkiewicz M.; RT "Mammalian subtilisin/kexin isozyme SKI-1: a widely expressed proprotein RT convertase with a unique cleavage specificity and cellular localization."; RL Proc. Natl. Acad. Sci. U.S.A. 96:1321-1326(1999). RN [9] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF HIS-249. RX PubMed=12782636; DOI=10.1074/jbc.m300923200; RA Okada T., Haze K., Nadanaka S., Yoshida H., Seidah N.G., Hirano Y., RA Sato R., Negishi M., Mori K.; RT "A serine protease inhibitor prevents endoplasmic reticulum stress-induced RT cleavage but not transport of the membrane-bound transcription factor RT ATF6."; RL J. Biol. Chem. 278:31024-31032(2003). RN [10] 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 [11] RP FUNCTION. RX PubMed=21719679; DOI=10.1126/science.1205677; RA Marschner K., Kollmann K., Schweizer M., Braulke T., Pohl S.; RT "A key enzyme in the biogenesis of lysosomes is a protease that regulates RT cholesterol metabolism."; RL Science 333:87-90(2011). RN [12] RP PHOSPHORYLATION AT SER-168. RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028; RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., RA Pinna L.A., Pagliarini D.J., Dixon J.E.; RT "A single kinase generates the majority of the secreted phosphoproteome."; RL Cell 161:1619-1632(2015). RN [13] RP FUNCTION, INVOLVEMENT IN SEDKF, MUTAGENESIS OF SER-414, AND VARIANT SEDKF RP GLY-365. RX PubMed=30046013; DOI=10.1172/jci.insight.121596; RA Kondo Y., Fu J., Wang H., Hoover C., McDaniel J.M., Steet R., Patra D., RA Song J., Pollard L., Cathey S., Yago T., Wiley G., Macwana S., RA Guthridge J., McGee S., Li S., Griffin C., Furukawa K., James J.A., RA Ruan C., McEver R.P., Wierenga K.J., Gaffney P.M., Xia L.; RT "Site-1 protease deficiency causes human skeletal dysplasia due to RT defective inter-organelle protein trafficking."; RL JCI Insight 3:0-0(2018). RN [14] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH FAM20C, SUBCELLULAR RP LOCATION, AND MUTAGENESIS OF SER-414. RX PubMed=34349020; DOI=10.1073/pnas.2100133118; RA Chen X., Zhang J., Liu P., Wei Y., Wang X., Xiao J., Wang C.C., Wang L.; RT "Proteolytic processing of secretory pathway kinase Fam20C by site-1 RT protease promotes biomineralization."; RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021). RN [15] RP INTERACTION WITH LYSET. RX PubMed=36096887; DOI=10.1038/s41467-022-33025-1; RA Zhang W., Yang X., Li Y., Yu L., Zhang B., Zhang J., Cho W.J., RA Venkatarangan V., Chen L., Burugula B.B., Bui S., Wang Y., Duan C., RA Kitzman J.O., Li M.; RT "GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6- RT phosphate pathway."; RL Nat. Commun. 13:5351-5351(2022). RN [16] RP VARIANT SEDKF ARG-878. RX PubMed=36330313; DOI=10.1155/2022/5498109; RA Alotaibi M., Aldossari A., Khan I., Alotaibi L.; RT "Identification of a New Variant of the MBTPS1 Gene of the Kondo-Fu Type of RT Spondyloepiphyseal Dysplasia (SEDKF) in a Saudi Patient."; RL Case Rep. Pediatr. 2022:5498109-5498109(2022). CC -!- FUNCTION: Serine protease that cleaves after hydrophobic or small CC residues, provided that Arg or Lys is in position P4: known substrates CC include SREBF1/SREBP1, SREBF2/SREBP2, BDNF, GNPTAB, ATF6, ATF6B and CC FAM20C (PubMed:10644685, PubMed:12782636, PubMed:21719679, CC PubMed:34349020). Cleaves substrates after Arg-Ser-Val-Leu (SREBP2), CC Arg-His-Leu-Leu (ATF6), Arg-Gly-Leu-Thr (BDNF) and its own propeptide CC after Arg-Arg-Leu-Leu (PubMed:10644685, PubMed:21719679). Catalyzes the CC first step in the proteolytic activation of the sterol regulatory CC element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 CC (PubMed:12782636). Also mediates the first step in the proteolytic CC activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 CC and ATF6B) (PubMed:12782636). Mediates the protein cleavage of GNPTAB CC into subunit alpha and beta, thereby participating in biogenesis of CC lysosomes (PubMed:21719679). Cleaves the propeptide from FAM20C which CC is required for FAM20C secretion from the Golgi apparatus membrane and CC for enhancement of FAM20C kinase activity, promoting osteoblast CC differentiation and biomineralization (PubMed:34349020). Involved in CC the regulation of M6P-dependent Golgi-to-lysosome trafficking of CC lysosomal enzymes (PubMed:21719679, PubMed:30046013). It is required CC for the activation of CREB3L2/BBF2H7, a transcriptional activator of CC MIA3/TANGO and other genes controlling mega vesicle formation CC (PubMed:30046013). Therefore, it plays a key role in the regulation of CC mega vesicle-mediated collagen trafficking (PubMed:30046013). In CC astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the CC first step of the regulated intramembrane proteolytic activation of the CC transcription factor CREB3L1, leading to the inhibition of cell-cycle CC progression (PubMed:16417584). {ECO:0000269|PubMed:10644685, CC ECO:0000269|PubMed:12782636, ECO:0000269|PubMed:16417584, CC ECO:0000269|PubMed:21719679, ECO:0000269|PubMed:30046013, CC ECO:0000269|PubMed:34349020}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Processes precursors containing basic and CC hydrophobic/aliphatic residues at P4 and P2, respectively, with a CC relatively relaxed acceptance of amino acids at P1 and P3.; CC EC=3.4.21.112; Evidence={ECO:0000269|PubMed:10644685, CC ECO:0000269|PubMed:12782636, ECO:0000269|PubMed:21719679, CC ECO:0000269|PubMed:34349020}; CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:10644685}; CC -!- ACTIVITY REGULATION: Inhibited by divalent copper and zinc ions, but CC not by nickel or cobalt (PubMed:10644685). Inhibited by its prosegment, CC but not smaller fragments (PubMed:10644685). Inhibited by 4-(2- CC aminoethyl)benzenesulfonyl fluoride (AEBSF), a serine protease CC inhibitor (PubMed:12782636). {ECO:0000269|PubMed:10644685, CC ECO:0000269|PubMed:12782636}. CC -!- SUBUNIT: Interacts with LYSET; this interaction bridges GNPTAB to CC MBTPS1. {ECO:0000269|PubMed:36096887}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:9990022}; Single-pass type I membrane protein CC {ECO:0000269|PubMed:9990022}. Golgi apparatus membrane CC {ECO:0000269|PubMed:34349020, ECO:0000269|PubMed:9990022}; Single-pass CC type I membrane protein {ECO:0000269|PubMed:9990022}. Note=May sort to CC other organelles, including lysosomal and/or endosomal compartments. CC {ECO:0000269|PubMed:9990022}. CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:10944850}. CC -!- INDUCTION: Down-regulated by sterols. {ECO:0000269|PubMed:10944850}. CC -!- PTM: The 148 kDa zymogen is processed progressively into two membrane- CC bound 120 and 106 kDa forms in the endoplasmic reticulum, and late into CC a secreted 98 kDa form (PubMed:10644685). The propeptide is CC autocatalytically removed through an intramolecular cleavage after Leu- CC 186. Further cleavage generates 14, 10, and 8 kDa intermediates CC (PubMed:10644685). {ECO:0000269|PubMed:10644685}. CC -!- DISEASE: Spondyloepiphyseal dysplasia, Kondo-Fu type (SEDKF) CC [MIM:618392]: A disorder characterized by severely retarded growth, CC spondyloepiphyseal dysplasia, reduced bone mineral density, and CC markedly elevated plasma levels of various lysosomal enzymes. CC Additional features include pectus carinatum, kyphosis, a waddling CC gait, brachydactyly and dysmorphic facial features. SEDKF transmission CC pattern is consistent with autosomal recessive inheritance. CC {ECO:0000269|PubMed:30046013, ECO:0000269|PubMed:36330313}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the peptidase S8 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA07653.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={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; D42053; BAA07653.2; ALT_INIT; mRNA. DR EMBL; AK291773; BAF84462.1; -; mRNA. DR EMBL; AC040169; -; NOT_ANNOTATED_CDS; Genomic_RNA. DR EMBL; BC114555; AAI14556.1; -; mRNA. DR EMBL; BC114961; AAI14962.1; -; mRNA. DR EMBL; AL133583; CAB63727.1; -; mRNA. DR CCDS; CCDS10941.1; -. DR PIR; T43492; T43492. DR RefSeq; NP_003782.1; NM_003791.3. DR AlphaFoldDB; Q14703; -. DR SMR; Q14703; -. DR BioGRID; 114259; 128. DR IntAct; Q14703; 13. DR MINT; Q14703; -. DR STRING; 9606.ENSP00000344223; -. DR BindingDB; Q14703; -. DR ChEMBL; CHEMBL5916; -. DR GuidetoPHARMACOLOGY; 2381; -. DR MEROPS; S08.063; -. DR GlyConnect; 1500; 1 N-Linked glycan (1 site). DR GlyCosmos; Q14703; 6 sites, 1 glycan. DR GlyGen; Q14703; 11 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (5 sites). DR iPTMnet; Q14703; -. DR PhosphoSitePlus; Q14703; -. DR BioMuta; MBTPS1; -. DR DMDM; 17368466; -. DR EPD; Q14703; -. DR jPOST; Q14703; -. DR MassIVE; Q14703; -. DR MaxQB; Q14703; -. DR PaxDb; 9606-ENSP00000344223; -. DR PeptideAtlas; Q14703; -. DR ProteomicsDB; 60141; -. DR Pumba; Q14703; -. DR Antibodypedia; 1735; 160 antibodies from 24 providers. DR DNASU; 8720; -. DR Ensembl; ENST00000343411.8; ENSP00000344223.3; ENSG00000140943.18. DR GeneID; 8720; -. DR KEGG; hsa:8720; -. DR MANE-Select; ENST00000343411.8; ENSP00000344223.3; NM_003791.4; NP_003782.1. DR UCSC; uc002fhi.5; human. DR AGR; HGNC:15456; -. DR CTD; 8720; -. DR DisGeNET; 8720; -. DR GeneCards; MBTPS1; -. DR HGNC; HGNC:15456; MBTPS1. DR HPA; ENSG00000140943; Low tissue specificity. DR MalaCards; MBTPS1; -. DR MIM; 603355; gene. DR MIM; 618392; phenotype. DR neXtProt; NX_Q14703; -. DR OpenTargets; ENSG00000140943; -. DR PharmGKB; PA30671; -. DR VEuPathDB; HostDB:ENSG00000140943; -. DR eggNOG; KOG4266; Eukaryota. DR GeneTree; ENSGT00490000043404; -. DR HOGENOM; CLU_004504_1_0_1; -. DR InParanoid; Q14703; -. DR OMA; LEYTTTG; -. DR OrthoDB; 5606at2759; -. DR PhylomeDB; Q14703; -. DR TreeFam; TF324501; -. DR BRENDA; 3.4.21.112; 2681. DR PathwayCommons; Q14703; -. 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-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-HSA-8874177; ATF6B (ATF6-beta) activates chaperones. DR Reactome; R-HSA-8874211; CREB3 factors activate genes. DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation. DR Reactome; R-HSA-8963889; Assembly of active LPL and LIPC lipase complexes. DR SignaLink; Q14703; -. DR SIGNOR; Q14703; -. DR BioGRID-ORCS; 8720; 504 hits in 1184 CRISPR screens. DR ChiTaRS; MBTPS1; human. DR GenomeRNAi; 8720; -. DR Pharos; Q14703; Tchem. DR PRO; PR:Q14703; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q14703; Protein. DR Bgee; ENSG00000140943; Expressed in stromal cell of endometrium and 207 other cell types or tissues. DR ExpressionAtlas; Q14703; baseline and differential. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005794; C:Golgi apparatus; IBA:GO_Central. DR GO; GO:0000139; C:Golgi membrane; IDA:UniProt. DR GO; GO:0005795; C:Golgi stack; IEA:Ensembl. DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0036500; P:ATF6-mediated unfolded protein response; TAS:ParkinsonsUK-UCL. DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; TAS:Reactome. DR GO; GO:0007040; P:lysosome organization; IMP:UniProtKB. DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; ISS:ParkinsonsUK-UCL. DR GO; GO:0007095; P:mitotic G2 DNA damage checkpoint signaling; IEA:Ensembl. DR GO; GO:0051604; P:protein maturation; IDA:UniProt. DR GO; GO:0016485; P:protein processing; IDA:UniProtKB. DR GO; GO:0006508; P:proteolysis; IMP:UniProtKB. DR GO; GO:0045540; P:regulation of cholesterol biosynthetic process; TAS:Reactome. DR GO; GO:0060627; P:regulation of vesicle-mediated transport; IMP:UniProtKB. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; ISS:ParkinsonsUK-UCL. DR CDD; cd07479; Peptidases_S8_SKI-1_like; 1. DR Gene3D; 3.40.50.200; Peptidase S8/S53 domain; 1. DR InterPro; IPR000209; Peptidase_S8/S53_dom. DR InterPro; IPR036852; Peptidase_S8/S53_dom_sf. DR InterPro; IPR022398; Peptidase_S8_His-AS. DR InterPro; IPR023828; Peptidase_S8_Ser-AS. DR InterPro; IPR015500; Peptidase_S8_subtilisin-rel. DR InterPro; IPR034185; Site-1_peptidase_cat_dom. DR PANTHER; PTHR43806:SF7; MEMBRANE-BOUND TRANSCRIPTION FACTOR SITE-1 PROTEASE; 1. DR PANTHER; PTHR43806; PEPTIDASE S8; 1. DR Pfam; PF00082; Peptidase_S8; 1. DR PRINTS; PR00723; SUBTILISIN. DR SUPFAM; SSF52743; Subtilisin-like; 1. DR PROSITE; PS51892; SUBTILASE; 1. DR PROSITE; PS00137; SUBTILASE_HIS; 1. DR PROSITE; PS00138; SUBTILASE_SER; 1. DR Genevisible; Q14703; HS. PE 1: Evidence at protein level; KW Autocatalytic cleavage; Calcium; Cholesterol metabolism; KW Direct protein sequencing; Disease variant; Dwarfism; KW Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Hydrolase; KW Lipid metabolism; Membrane; Phosphoprotein; Protease; Reference proteome; KW Serine protease; Signal; Steroid metabolism; Sterol metabolism; KW Transmembrane; Transmembrane helix; Zymogen. FT SIGNAL 1..17 FT PROPEP 18..186 FT /id="PRO_0000027051" FT CHAIN 187..1052 FT /note="Membrane-bound transcription factor site-1 protease" FT /id="PRO_0000027052" FT TOPO_DOM 187..998 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 999..1021 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1022..1052 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 190..472 FT /note="Peptidase S8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT REGION 877..899 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1027..1052 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 877..891 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 218 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT ACT_SITE 249 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT ACT_SITE 414 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT SITE 186..187 FT /note="Cleavage; by autolysis" FT /evidence="ECO:0000269|PubMed:10644685" FT MOD_RES 168 FT /note="Phosphoserine; by FAM20C" FT /evidence="ECO:0000269|PubMed:26091039" FT CARBOHYD 236 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 305 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 515 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 728 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 939 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 6 FT /note="I -> T (in dbSNP:rs34701895)" FT /id="VAR_051822" FT VARIANT 90 FT /note="R -> G (in dbSNP:rs34076105)" FT /id="VAR_051823" FT VARIANT 365 FT /note="D -> G (in SEDKF; due to a nucleotide substitution FT that creates a dominant splice donor site in exon 9; two FT different type of transcripts are produced, a major FT non-functional alternatively spliced transcript with a FT 41-bp deletion of exon 9, loss of S-414 in the catalytic FT triad and premature truncation and a normally spliced FT transcript with variant G-365; the transcript with G-365 FT produces a catalytically active protein but is the less FT abundant; dbSNP:rs1226321681)" FT /evidence="ECO:0000269|PubMed:30046013" FT /id="VAR_082197" FT VARIANT 878 FT /note="S -> R (in SEDKF; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36330313" FT /id="VAR_087565" FT MUTAGEN 249 FT /note="H->A: Abolishes serine protease activity." FT /evidence="ECO:0000269|PubMed:12782636" FT MUTAGEN 414 FT /note="S->A: Abolishes serine protease activity. Does not FT promote FAM20C kinase activity." FT /evidence="ECO:0000269|PubMed:30046013, FT ECO:0000269|PubMed:34349020" FT CONFLICT 843 FT /note="L -> Q (in Ref. 3; BAF84462)" FT /evidence="ECO:0000305" SQ SEQUENCE 1052 AA; 117749 MW; CA6F013588595B45 CRC64; MKLVNIWLLL LVVLLCGKKH LGDRLEKKSF EKAPCPGCSH LTLKVEFSST VVEYEYIVAF NGYFTAKARN SFISSALKSS EVDNWRIIPR NNPSSDYPSD FEVIQIKEKQ KAGLLTLEDH PNIKRVTPQR KVFRSLKYAE SDPTVPCNET RWSQKWQSSR PLRRASLSLG SGFWHATGRH SSRRLLRAIP RQVAQTLQAD VLWQMGYTGA NVRVAVFDTG LSEKHPHFKN VKERTNWTNE RTLDDGLGHG TFVAGVIASM RECQGFAPDA ELHIFRVFTN NQVSYTSWFL DAFNYAILKK IDVLNLSIGG PDFMDHPFVD KVWELTANNV IMVSAIGNDG PLYGTLNNPA DQMDVIGVGG IDFEDNIARF SSRGMTTWEL PGGYGRMKPD IVTYGAGVRG SGVKGGCRAL SGTSVASPVV AGAVTLLVST VQKRELVNPA SMKQALIASA RRLPGVNMFE QGHGKLDLLR AYQILNSYKP QASLSPSYID LTECPYMWPY CSQPIYYGGM PTVVNVTILN GMGVTGRIVD KPDWQPYLPQ NGDNIEVAFS YSSVLWPWSG YLAISISVTK KAASWEGIAQ GHVMITVASP AETESKNGAE QTSTVKLPIK VKIIPTPPRS KRVLWDQYHN LRYPPGYFPR DNLRMKNDPL DWNGDHIHTN FRDMYQHLRS MGYFVEVLGA PFTCFDASQY GTLLMVDSEE EYFPEEIAKL RRDVDNGLSL VIFSDWYNTS VMRKVKFYDE NTRQWWMPDT GGANIPALNE LLSVWNMGFS DGLYEGEFTL ANHDMYYASG CSIAKFPEDG VVITQTFKDQ GLEVLKQETA VVENVPILGL YQIPAEGGGR IVLYGDSNCL DDSHRQKDCF WLLDALLQYT SYGVTPPSLS HSGNRQRPPS GAGSVTPERM EGNHLHRYSK VLEAHLGDPK PRPLPACPRL SWAKPQPLNE TAPSNLWKHQ KLLSIDLDKV VLPNFRSNRP QVRPLSPGES GAWDIPGGIM PGRYNQEVGQ TIPVFAFLGA MVVLAFFVVQ INKAKSRPKR RKPRVKRPQL MQQVHPPKTP SV //