MBTPS1

The encoded protein has a central role in the regulation of lipid metabolism in cells. It is a sterol-regulated subtilisin-like serine protease that cleaves ER membrane-bound sterol regulatory element-binding proteins (SREBPs), a reaction that initiates the two-step proteolytic process by which transcriptionally active fragments of SREBPs are released from the membrane for translocation to the nucleus. The gene product is an integral membrane ER protein, with the bulk located in the ER lumen. It is synthesized as an inactive preproprotein that is self-activated by an intramolecular cleavage that generates the mature protein. [provided by RefSeq]

Full Name

membrane-bound transcription factor peptidase, site 1

Function

Serine protease that cleaves after hydrophobic or small residues, provided that Arg or Lys is in position P4: known substrates are SREBF1/SREBP1, SREBF2/SREBP2, BDNF, GNPTAB, ATF6 and ATF6B (PubMed:10644685, PubMed:12782636, PubMed:21719679).

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).

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).

Biological Process

ATF6-mediated unfolded protein response Source: ParkinsonsUK-UCL
Cholesterol metabolic process Source: UniProtKB-KW
Endoplasmic reticulum unfolded protein response Source: Reactome
Lysosome organization Source: UniProtKB
Membrane protein intracellular domain proteolysis Source: ParkinsonsUK-UCL
Proteolysis Source: UniProtKB
Regulation of cholesterol biosynthetic process Source: Reactome
Regulation of vesicle-mediated transport Source: UniProtKB
Response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL

Cellular Location

Golgi apparatus
Golgi apparatus membrane
Endoplasmic reticulum
Endoplasmic reticulum membrane
Note: May sort to other organelles, including lysosomal and/or endosomal compartments.

Involvement in disease

Spondyloepiphyseal dysplasia, Kondo-Fu type (SEDKF):
A disorder characterized by severely retarded growth, spondyloepiphyseal dysplasia, reduced bone mineral density, and markedly elevated plasma levels of various lysosomal enzymes. Additional features include pectus carinatum, kyphosis, a waddling gait, brachydactyly and dysmorphic facial features. SEDKF transmission pattern is consistent with autosomal recessive inheritance.

Topology

Lumenal: 187-998
Helical: 999-1021
Cytoplasmic: 1022-1052

PTM

The 148 kDa zymogen is processed progressively into two membrane-bound 120 and 106 kDa forms in the endoplasmic reticulum, and late into a secreted 98 kDa form (PubMed:10644685). The propeptide is autocatalytically removed through an intramolecular cleavage after Leu-186. Further cleavage generates 14, 10, and 8 kDa intermediates (PubMed:10644685).