8uwc

Structural highlights

Disease

MBTP1_HUMAN The disease is caused by variants affecting the gene represented in this entry.

Function

MBTP1_HUMAN Serine protease that cleaves after hydrophobic or small residues, provided that Arg or Lys is in position P4: known substrates include SREBF1/SREBP1, SREBF2/SREBP2, BDNF, GNPTAB, ATF6, ATF6B and FAM20C (PubMed:10644685, PubMed:12782636, PubMed:21719679, PubMed:34349020). Cleaves substrates after Arg-Ser-Val-Leu (SREBP2), Arg-His-Leu-Leu (ATF6), Arg-Gly-Leu-Thr (BDNF) and its own propeptide after Arg-Arg-Leu-Leu (PubMed:10644685, PubMed:21719679). Catalyzes the first step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:12782636). Also mediates the first step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:12782636). Mediates the protein cleavage of GNPTAB into subunit alpha and beta, thereby participating in biogenesis of lysosomes (PubMed:21719679). Cleaves the propeptide from FAM20C which is required for FAM20C secretion from the Golgi apparatus membrane and for enhancement of FAM20C kinase activity, promoting osteoblast differentiation and biomineralization (PubMed:34349020). Involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes (PubMed:21719679, PubMed:30046013). It is required for the activation of CREB3L2/BBF2H7, a transcriptional activator of MIA3/TANGO and other genes controlling mega vesicle formation (PubMed:30046013). Therefore, it plays a key role in the regulation of mega vesicle-mediated collagen trafficking (PubMed:30046013). In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the first step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression (PubMed:16417584).^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Touré BB, Munzer JS, Basak A, Benjannet S, Rochemont J, Lazure C, Chrétien M, Seidah NG. Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. J Biol Chem. 2000 Jan 28;275(4):2349-58. PMID:10644685 doi:10.1074/jbc.275.4.2349
2. ↑ Okada T, Haze K, Nadanaka S, Yoshida H, Seidah NG, Hirano Y, Sato R, Negishi M, Mori K. A serine protease inhibitor prevents endoplasmic reticulum stress-induced cleavage but not transport of the membrane-bound transcription factor ATF6. J Biol Chem. 2003 Aug 15;278(33):31024-32. PMID:12782636 doi:10.1074/jbc.M300923200
3. ↑ Murakami T, Kondo S, Ogata M, Kanemoto S, Saito A, Wanaka A, Imaizumi K. Cleavage of the membrane-bound transcription factor OASIS in response to endoplasmic reticulum stress. J Neurochem. 2006 Feb;96(4):1090-100. PMID:16417584 doi:10.1111/j.1471-4159.2005.03596.x
4. ↑ Marschner K, Kollmann K, Schweizer M, Braulke T, Pohl S. A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism. Science. 2011 Jul 1;333(6038):87-90. PMID:21719679 doi:10.1126/science.1205677
5. ↑ Kondo Y, Fu J, Wang H, Hoover C, McDaniel JM, Steet R, Patra D, Song J, Pollard L, Cathey S, Yago T, Wiley G, Macwana S, Guthridge J, McGee S, Li S, Griffin C, Furukawa K, James JA, Ruan C, McEver RP, Wierenga KJ, Gaffney PM, Xia L. Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking. JCI Insight. 2018 Jul 26;3(14):e121596. PMID:30046013 doi:10.1172/jci.insight.121596
6. ↑ Chen X, Zhang J, Liu P, Wei Y, Wang X, Xiao J, Wang CC, Wang L. Proteolytic processing of secretory pathway kinase Fam20C by site-1 protease promotes biomineralization. Proc Natl Acad Sci U S A. 2021 Aug 10;118(32):e2100133118. PMID:34349020 doi:10.1073/pnas.2100133118