MBTP1_CRIGR
ID MBTP1_CRIGR Reviewed; 1052 AA.
AC Q9Z2A8; G3GRY2;
DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 2.
DT 03-AUG-2022, entry version 116.
DE RecName: Full=Membrane-bound transcription factor site-1 protease {ECO:0000305};
DE EC=3.4.21.112;
DE AltName: Full=Endopeptidase S1P {ECO:0000303|PubMed:9809072};
DE AltName: Full=Sterol-regulated luminal protease {ECO:0000303|PubMed:9809072};
DE Flags: Precursor;
GN Name=MBTPS1 {ECO:0000250|UniProtKB:Q14703};
GN Synonyms=S1P {ECO:0000303|PubMed:9809072};
OS Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Cricetulus.
OX NCBI_TaxID=10029;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, INDUCTION, AND
RP MUTAGENESIS OF ASP-218; HIS-249 AND SER-414.
RC TISSUE=Ovary;
RX PubMed=9809072; DOI=10.1016/s1097-2765(00)80150-1;
RA Sakai J., Rawson R.B., Espenshade P.J., Cheng D., Seegmiller A.C.,
RA Goldstein J.L., Brown M.S.;
RT "Molecular identification of the sterol-regulated luminal protease that
RT cleaves SREBPs and controls lipid composition of animal cells.";
RL Mol. Cell 2:505-514(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=21804562; DOI=10.1038/nbt.1932;
RA Xu X., Nagarajan H., Lewis N.E., Pan S., Cai Z., Liu X., Chen W., Xie M.,
RA Wang W., Hammond S., Andersen M.R., Neff N., Passarelli B., Koh W.,
RA Fan H.C., Wang J., Gui Y., Lee K.H., Betenbaugh M.J., Quake S.R.,
RA Famili I., Palsson B.O., Wang J.;
RT "The genomic sequence of the Chinese hamster ovary (CHO)-K1 cell line.";
RL Nat. Biotechnol. 29:735-741(2011).
RN [3]
RP FUNCTION.
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).
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:9809072, PubMed:11163209). Cleaves substrates after Arg-
CC Ser-Val-Leu (SREBP2), Arg-His-Leu-Leu (ATF6), Arg-Gly-Leu-Thr (BDNF)
CC and its own propeptide after Arg-Arg-Leu-Leu (PubMed:9809072,
CC PubMed:11163209). Catalyzes the first step in the proteolytic
CC activation of the sterol regulatory element-binding proteins (SREBPs)
CC SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:9809072). Also mediates the
CC first step in the proteolytic activation of the cyclic AMP-dependent
CC transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:11163209). Mediates
CC the protein cleavage of GNPTAB into subunit alpha and beta, thereby
CC participating in biogenesis of lysosomes (By similarity). Cleaves the
CC propeptide from FAM20C which is required for FAM20C secretion from the
CC Golgi apparatus membrane and for enhancement of FAM20C kinase activity,
CC promoting osteoblast differentiation and biomineralization (By
CC similarity). Involved in the regulation of M6P-dependent Golgi-to-
CC lysosome trafficking of lysosomal enzymes (By similarity). It is
CC required for the activation of CREB3L2/BBF2H7, a transcriptional
CC activator of MIA3/TANGO and other genes controlling mega vesicle
CC formation (By similarity). Therefore, it plays a key role in the
CC regulation of mega vesicle-mediated collagen trafficking (By
CC similarity). {ECO:0000250|UniProtKB:Q14703,
CC ECO:0000269|PubMed:11163209, ECO:0000269|PubMed:9809072}.
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:9809072};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000250|UniProtKB:Q14703};
CC -!- ACTIVITY REGULATION: Inhibited by divalent copper and zinc ions, but
CC not by nickel or cobalt. Inhibited by its prosegment, but not smaller
CC fragments thereof. Inhibited by 4-(2-aminoethyl)benzenesulfonyl
CC fluoride (AEBSF), a serine protease inhibitor.
CC {ECO:0000250|UniProtKB:Q14703}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q14703}; Single-pass type I membrane protein
CC {ECO:0000255}. Golgi apparatus membrane {ECO:0000250|UniProtKB:Q14703};
CC Single-pass type I membrane protein {ECO:0000255}. Note=May sort to
CC other organelles, including lysosomal and/or endosomal compartments.
CC {ECO:0000250|UniProtKB:Q14703}.
CC -!- INDUCTION: Down-regulated by sterols. {ECO:0000269|PubMed:9809072}.
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. The propeptide is autocatalytically removed
CC through an intramolecular cleavage after Leu-186. Further cleavage
CC generates 14, 10, and 8 kDa intermediates.
CC {ECO:0000250|UniProtKB:Q14703}.
CC -!- SIMILARITY: Belongs to the peptidase S8 family. {ECO:0000305}.
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DR EMBL; AF078105; AAC78321.1; -; mRNA.
DR EMBL; JH000004; EGV94126.1; -; Genomic_DNA.
DR PIR; T17093; T17093.
DR RefSeq; NP_001233611.1; NM_001246682.1.
DR AlphaFoldDB; Q9Z2A8; -.
DR SMR; Q9Z2A8; -.
DR STRING; 10029.NP_001233611.1; -.
DR MEROPS; S08.063; -.
DR PRIDE; Q9Z2A8; -.
DR Ensembl; ENSCGRT00001029099; ENSCGRP00001024853; ENSCGRG00001022644.
DR GeneID; 100689417; -.
DR KEGG; cge:100689417; -.
DR CTD; 8720; -.
DR eggNOG; KOG4266; Eukaryota.
DR GeneTree; ENSGT00490000043404; -.
DR OMA; MKFANIW; -.
DR OrthoDB; 340650at2759; -.
DR BRENDA; 3.4.21.112; 1309.
DR Proteomes; UP000001075; Unassembled WGS sequence.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005795; C:Golgi stack; IEA:Ensembl.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0004252; F:serine-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0007040; P:lysosome organization; ISS:UniProtKB.
DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; IMP:ParkinsonsUK-UCL.
DR GO; GO:0016485; P:protein processing; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; ISS:UniProtKB.
DR GO; GO:0060627; P:regulation of vesicle-mediated transport; IEA:Ensembl.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL.
DR CDD; cd07479; Peptidases_S8_SKI-1_like; 1.
DR Gene3D; 3.40.50.200; -; 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 Pfam; PF00082; Peptidase_S8; 1.
DR PRINTS; PR00723; SUBTILISIN.
DR SUPFAM; SSF52743; SSF52743; 1.
DR PROSITE; PS51892; SUBTILASE; 1.
DR PROSITE; PS00137; SUBTILASE_HIS; 1.
DR PROSITE; PS00138; SUBTILASE_SER; 1.
PE 1: Evidence at protein level;
KW Autocatalytic cleavage; Calcium; Cholesterol metabolism;
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 /evidence="ECO:0000255"
FT PROPEP 18..186
FT /evidence="ECO:0000255"
FT /id="PRO_0000027049"
FT CHAIN 187..1052
FT /note="Membrane-bound transcription factor site-1 protease"
FT /id="PRO_0000027050"
FT TOPO_DOM 187..999
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 1000..1022
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1023..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..900
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1025..1052
FT /note="Disordered"
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:0000250|UniProtKB:Q14703"
FT MOD_RES 168
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14703"
FT CARBOHYD 148
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
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 MUTAGEN 218
FT /note="D->N: Loss of activity."
FT /evidence="ECO:0000269|PubMed:9809072"
FT MUTAGEN 249
FT /note="H->F: Loss of activity."
FT /evidence="ECO:0000269|PubMed:9809072"
FT MUTAGEN 414
FT /note="S->A: Loss of activity."
FT /evidence="ECO:0000269|PubMed:9809072"
FT CONFLICT 875
FT /note="T -> N (in Ref. 1; AAC78321)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1052 AA; 117552 MW; 7DD079393815BAED CRC64;
MKLINIWLLL LVVLLCGKKH LGDRLGKKAF EKASCPSCSH LTLKVEFSST VVEYEYIVAF
NGYFTAKARN SFISSALKSS EVDNWRIIPR NNPSSDYPSD FEVIQIKEKQ KAGLLTLEDH
PNIKRVTPQR KVFRSLKFAE SDPIVPCNET RWSQKWQSSR PLRRASLSLG SGFWHATGRH
SSRRLLRAIP RQVAQTLQAD VLWQMGYTGA NVRVAVFDTG LSEKHPHFKN VKERTNWTNE
RTLDDGLGHG TFVAGVIASM RECQGFAPDA ELHIFRVFTN NQVSYTSWFL DAFNYAILKK
IDVLNLSIGG PDFMDHPFVD KVWELTANNV IMVSAIGNDG PLYGTLNNPA DQMDVIGVGG
IDFEDNIARF SSRGMTTWEL PGGYGRVKPD IVTYGAGVRG SGVKGGCRAL SGTSVASPVV
AGAVTLLVST VQKRELVNPA SVKQALIASA RRLPGVNMFE QGHGKLDLLR AYQILSSYKP
QASLSPSYID LTECPYMWPY CSQPIYYGGM PTIVNVTILN GMGVTGRIVD KPEWRPYLPQ
NGDNIEVAFS YSSVLWPWSG YLAISISVTK KAASWEGIAQ GHIMITVASP AETEAKNGAE
HTSTVKLPIK VKIIPTPPRS KRVLWDQYHN LRYPPGYFPR DNLRMKNDPL DWNGDHVHTN
FRDMYQHLRS MGYFVEVLGA PFTCFDATQY GTLLMVDSEE EYFPEEIAKL RRDVDNGLSL
VIFSDWYNTS VMRKVKFYDE NTRQWWMPDT GGANIPALNE LLSVWNMGFS DGLYEGEFAL
ANHDMYYASG CSIAKFPEDG VVITQTFKDQ GLEVLKQETA VVENVPILGL YQIPAEGGGR
IVLYGDSNCL DDSHRQKDCF WLLDALLQYT SYGVTPPSLS HSGNRQRPPS GAGLAPPERM
EGNHLHRYSK VLEAHLGDPK PRPLPACPHL SWAKPQPLNE TAPSNLWKHQ KLLSIDLDKV
VLPNFRSNRP QVRPLSPGES GAWDIPGGIM PGRYNQEVGQ TIPVFAFLGA MVALAFFVVQ
ISKAKSRPKR RRPRAKRPQL TQQTHPPRTP SV
