PIGS (Q96S52) review notes

Summary of verified biology

PIGS is the PIG-S subunit of the GPI transamidase (GPI-T) complex (a.k.a.
phosphatidylinositol-glycan biosynthesis class S protein). GPI-T is an ER membrane,
equimolar heteropentameric complex of PIGK, GPAA1, PIGT, PIGS and PIGU that
post-translationally attaches a pre-assembled GPI anchor to the C-terminus of GPI-anchored
proteins, replacing the C-terminal GPI-attachment signal peptide.

• PIGK is the catalytic (cysteine-protease/transaminase-like) subunit; the catalytic
  triad is C206-H164-N58 PMID:35165458. GPAA1 (M28-peptidase-like) is proposed to
  form the amide bond with the bridging EtNP.
• PIGS is a required, non-catalytic accessory subunit — "PIGS is an indispensable
  subunit of GPI-TA activity, although its role is unclear" PMID:34576938. Loss of any
  one subunit abolishes activity.
• Topology: multi-pass ER membrane protein; N-terminal TM (19-39) and C-terminal TM
  (518-532), large lumenal domain (40-517) [UniProt; PMID:35165458, PMID:35551457].
• Structures: human GPI-T cryo-EM (PDB 7W72 PMID:35165458, 7WLD PMID:35551457,
  8IMX/8IMY liganded PMID:37684232).

Provenance for key claims

• Complex membership + 4 named partners: [PMID:11483512 "we report two new components of
  this enzyme: PIG-S and PIG-T"; "PIG-S and PIG-T form a protein complex with GAA1 and
  GPI8"]. Fifth subunit PIG-U added in PMID:12802054.
• ER localization of GPI-T: PMID:15713669; PMID:12582175; cryo-EM structures place complex in ER membrane
  [PMID:35165458, PMID:35551457].
• Function of the complex: PMID:11483512.
• PIGS required for activity: PMID:34576938; PIGS/PIGT knockout cells defective in GPI
  transfer PMID:11483512.
• Disease: GPIBD18 (autosomal recessive; developmental delay, seizures, hypotonia)
  [PMID:30269814; UniProt DISEASE].

Annotation notes

• GOA carries NO catalytic MF term for PIGS. The only MF is protein binding (GO:0005515),
  from IntAct/large-scale interactome IPIs (PIGT partner Q969N2, plus keratin-associated
  proteins and other proteins from binary screens). These are uninformative and
  over-annotate a subunit whose real role is complex membership -> MARK_AS_OVER_ANNOTATED
  (per policy: do not REMOVE bare protein-binding IPIs).
• Core BP: GPI anchor biosynthetic process (GO:0006506) and attachment of GPI anchor to
  protein (GO:0016255) / GPI anchored protein biosynthesis (GO:0180046) — all accept.
• Core CC: GPI-anchor transamidase complex (GO:0042765); ER membrane (GO:0005789).
• membrane (GO:0016020, HDA, NK-cell membrane proteome PMID:19946888) is a correct but
  unspecific location -> MARK_AS_OVER_ANNOTATED (ER membrane is the informative term).
• Because PIGS is non-catalytic and GOA has no MF, core_functions omits molecular_function
  and instead uses directly_involved_in (BP) + locations (ER membrane) + in_complex (GPI-T).