MBTPS2 (S2P) review notes

Provenance / process

2026-10-18: Falcon deep research was attempted once in this session (for MBTPS1) and failed at
authentication ("Exception: Failed to authenticate"; key unauthorised / 403). Not retried for
MBTPS2. No -deep-research-*.md file exists; notes compiled manually from cached publications
(mostly abstract-only), UniProt and Reactome.

519 aa polytopic membrane protein; N and C termini cytosolic; "Belongs to the peptidase M50A
family" (UniProt; MEROPS M50.001; PANTHER PTHR13325:SF3).
Zinc metalloprotease with HEIGH motif within a hydrophobic segment and Asp467 as third zinc ligand
[PMID:10419520 "The HEIGH sequence of S2P, which contains two potential zinc-coordinating residues,
is contained within a long hydrophobic segment."; "Aspartic acid 467, located approximately 300
residues away from the HEIGH sequence, appears to provide the third coordinating residue for the
active site zinc."].
Cloned by complementation of CHO M19 cells PMID:9659902.

Second, sterol-independent cleavage of SREBP within TM1 after S1P PMID:8674110; cleaves Leu-Cys bond; needs
Asn-Pro helix-breaking motif in the substrate TM PMID:10805775.
Substrate must first be trimmed by S1P (S2P acts on short-lumenal-domain intermediates).
ATF6 second cleavage; S2P-null cells fail to induce GRP78 PMID:11163209.
Also OASIS/CREB3L1, CREB3L2, CREB3L3 (Reactome R-HSA-8874201) PMID:16417584.
Site of action: Golgi (Reactome; UniProt Golgi membrane by similarity/inference from PMID:16417584).

IFAP syndrome (X-linked) PMID:19361614; severity correlates with residual activity.
KFSD-X, X-linked Olmsted syndrome, and X-linked osteogenesis imperfecta type XIX PMID:27380894.
S2P is not needed for lysosomal enzyme trafficking (contrast with S1P/GNPTAB) PMID:30046013.

Core MF: metalloendopeptidase activity (GO:0004222) — ACCEPT all four rows.
Core BP: membrane protein intracellular domain proteolysis (GO:0031293) (ACCEPT IBA, IGI);
ATF6-mediated UPR (ACCEPT); positive regulation of cholesterol biosynthetic process (ACCEPT IDA;
"regulation of" TAS and "cholesterol metabolic process" TAS -> MODIFY to GO:0045542).
proteolysis IEA -> MODIFY to GO:0031293. protein maturation rows -> MODIFY to GO:0016485.
response to ER stress -> MODIFY to GO:0036500.
transcription regulator activator activity (IGI) -> MODIFY to GO:0004222: S2P is an enzyme
whose product is an active transcription factor; GO represents that as the catalytic activity.
positive regulation of transcription by RNA pol II (IGI) -> MARK_AS_OVER_ANNOTATED (two steps
removed, executed by released SREBP/ATF6 fragments).
Locations: Golgi membrane ACCEPT; cytoplasm (IBA/IDA/IEA) and membrane -> MODIFY to Golgi membrane.
bone maturation (IMP, OI19) -> KEEP_AS_NON_CORE.
regulation of response to ER stress (IBA, deep node with Arabidopsis S2P) -> KEEP_AS_NON_CORE.