MBTP1_MOUSE
ID MBTP1_MOUSE Reviewed; 1052 AA.
AC Q9WTZ2; Q6PG67;
DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Membrane-bound transcription factor site-1 protease {ECO:0000305};
DE EC=3.4.21.112 {ECO:0000269|PubMed:9990022};
DE AltName: Full=Endopeptidase S1P;
DE AltName: Full=Sterol-regulated luminal protease;
DE AltName: Full=Subtilisin/kexin isozyme 1 {ECO:0000303|PubMed:9990022};
DE Short=SKI-1 {ECO:0000303|PubMed:9990022};
DE Flags: Precursor;
GN Name=Mbtps1; Synonyms=S1p, Ski1 {ECO:0000303|PubMed:9990022};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=Pituitary;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Skin;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NMRI; TISSUE=Mammary gland, and Retina;
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 [4]
RP FUNCTION.
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).
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. Cleaves substrates after Arg-Ser-Val-Leu (SREBP2), Arg-His-Leu-
CC Leu (ATF6), Arg-Gly-Leu-Thr (BDNF) and its own propeptide after Arg-
CC Arg-Leu-Leu. Catalyzes the first step in the proteolytic activation of
CC the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1
CC and SREBF2/SREBP2. Also mediates the first step in the proteolytic
CC activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6
CC and ATF6B). Mediates the protein cleavage of GNPTAB into subunit alpha
CC and beta, thereby participating in biogenesis of lysosomes. 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
CC (PubMed:34349020). Involved in the regulation of M6P-dependent Golgi-
CC to-lysosome trafficking of lysosomal enzymes. It is required for the
CC activation of CREB3L2/BBF2H7, a transcriptional activator of MIA3/TANGO
CC and other genes controlling mega vesicle formation. Therefore, it plays
CC a key role in the regulation of mega vesicle-mediated collagen
CC trafficking. {ECO:0000250|UniProtKB:Q14703,
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:9990022};
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:0000269|PubMed:9990022};
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 -!- 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; AF094820; AAD27010.1; -; mRNA.
DR EMBL; AK029048; BAC26263.1; -; mRNA.
DR EMBL; BC054837; AAH54837.1; -; mRNA.
DR EMBL; BC057198; AAH57198.1; -; mRNA.
DR CCDS; CCDS22707.1; -.
DR RefSeq; NP_001161382.1; NM_001167910.1.
DR RefSeq; NP_062683.3; NM_019709.4.
DR RefSeq; XP_011246751.1; XM_011248449.2.
DR RefSeq; XP_011246752.1; XM_011248450.2.
DR AlphaFoldDB; Q9WTZ2; -.
DR SMR; Q9WTZ2; -.
DR BioGRID; 207992; 3.
DR STRING; 10090.ENSMUSP00000095965; -.
DR MEROPS; S08.063; -.
DR GlyGen; Q9WTZ2; 6 sites.
DR iPTMnet; Q9WTZ2; -.
DR PhosphoSitePlus; Q9WTZ2; -.
DR MaxQB; Q9WTZ2; -.
DR PaxDb; Q9WTZ2; -.
DR PRIDE; Q9WTZ2; -.
DR ProteomicsDB; 293435; -.
DR Antibodypedia; 1735; 133 antibodies from 24 providers.
DR DNASU; 56453; -.
DR Ensembl; ENSMUST00000081381; ENSMUSP00000080117; ENSMUSG00000031835.
DR Ensembl; ENSMUST00000098362; ENSMUSP00000095965; ENSMUSG00000031835.
DR GeneID; 56453; -.
DR KEGG; mmu:56453; -.
DR UCSC; uc009nps.2; mouse.
DR CTD; 8720; -.
DR MGI; MGI:1927235; Mbtps1.
DR VEuPathDB; HostDB:ENSMUSG00000031835; -.
DR eggNOG; KOG4266; Eukaryota.
DR GeneTree; ENSGT00490000043404; -.
DR HOGENOM; CLU_004504_1_0_1; -.
DR InParanoid; Q9WTZ2; -.
DR OMA; MKFANIW; -.
DR OrthoDB; 340650at2759; -.
DR PhylomeDB; Q9WTZ2; -.
DR TreeFam; TF324501; -.
DR Reactome; R-MMU-1655829; Regulation of cholesterol biosynthesis by SREBP (SREBF).
DR Reactome; R-MMU-381033; ATF6 (ATF6-alpha) activates chaperones.
DR Reactome; R-MMU-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-MMU-8874211; CREB3 factors activate genes.
DR Reactome; R-MMU-8957275; Post-translational protein phosphorylation.
DR BioGRID-ORCS; 56453; 28 hits in 74 CRISPR screens.
DR ChiTaRS; Mbtps1; mouse.
DR PRO; PR:Q9WTZ2; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q9WTZ2; protein.
DR Bgee; ENSMUSG00000031835; Expressed in saccule of membranous labyrinth and 268 other tissues.
DR Genevisible; Q9WTZ2; MM.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0005795; C:Golgi stack; IDA:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0004222; F:metalloendopeptidase activity; TAS:Reactome.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:MGI.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006629; P:lipid metabolic process; IMP:MGI.
DR GO; GO:0007040; P:lysosome organization; ISS:UniProtKB.
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; ISO:MGI.
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_0000027053"
FT CHAIN 187..1052
FT /note="Membrane-bound transcription factor site-1 protease"
FT /id="PRO_0000027054"
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 1026..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 CONFLICT 714
FT /note="V -> M (in Ref. 3; AAH57198)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1052 AA; 117457 MW; FBBD21C18775FD2A CRC64;
MKLVSTWLLV LVVLLCGKRH LGDRLGTRAL EKAPCPSCSH LTLKVEFSST VVEYEYIVAF
NGYFTAKARN SFISSALKSS EVENWRIIPR NNPSSDYPSD FEVIQIKEKQ KAGLLTLEDH
PNIKRVTPQR KVFRSLKFAE SNPIVPCNET RWSQKWQSSR PLKRASLSLG SGFWHATGRH
SSRRLLRAIP RQVAQTLQAD VLWQMGYTGA NVRVAVFDTG LSEKHPHFKN VKERTNWTNE
RTLDDGLGHG TFVAGVIASM RECQGFAPDA ELHIFRVFTN NQVSYTSWFL DAFNYAILKK
MDVLNLSIGG 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 AETELHSGAE
HTSTVKLPIK VKIIPTPPRS KRVLWDQYHN LRYPPGYFPR DNLRMKNDPL DWNGDHVHTN
FRDMYQHLRS MGYFVEVLGA PFTCFDATQY GTLLLVDSEE EYFPEEIAKL RRDVDNGLSL
VIFSDWYNTS VMRKVKFYDE NTRQWWMPDT GGANIPALNE LLSVWNMGFS DGLYEGEFVL
ANHDMYYASG CSIAKFPEDG VVITQTFKDQ GLEVLKQETA VVENVPILGL YQIPSEGGGR
IVLYGDSNCL DDSHRQKDCF WLLDALLQYT SYGVTPPSLS HSGNRQRPPS GAGLAPPERM
EGNHLHRYSK VLEAHLGDPK PRPLPACPHL SWAKPQPLNE TAPSNLWKHQ KLLSIDLDKV
VLPNFRSNRP QVRPLSPGES GAWDIPGGIM PGRYNQEVGQ TIPVFAFLGA MVALAFFVVQ
ISKAKSRPKR RRPRAKRPQL AQQAHPARTP SV
