id: Q96S52
gene_symbol: PIGS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGS (phosphatidylinositol-glycan biosynthesis class S protein) is a non-catalytic
  accessory subunit of the glycosylphosphatidylinositol-anchor transamidase (GPI-T) complex,
  an endoplasmic reticulum membrane enzyme complex. GPI-T is an equimolar heteropentamer 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 their C-terminal GPI-attachment
  signal peptide. Within the complex, PIGK is the catalytic (cysteine-protease/transaminase-like)
  subunit and GPAA1 forms the amide bond, whereas PIGS is an indispensable but non-catalytic
  subunit whose precise molecular role is not fully defined; loss of PIGS abolishes complex
  activity. PIGS is a multi-pass ER membrane glycoprotein with a large lumenal domain flanked
  by two transmembrane helices. Biallelic loss-of-function variants cause the autosomal
  recessive inherited GPI-deficiency disorder GPIBD18, presenting with severe developmental
  delay, seizures, hypotonia and dysmorphic features.
alternative_products:
- name: '1'
  id: Q96S52-1
- name: '2'
  id: Q96S52-2
  sequence_note: VSP_013158
existing_annotations:
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically-inferred involvement in attachment of GPI anchor to protein.
      This is the accepted core biological process for PIGS as a required subunit of the GPI
      transamidase complex, and is well supported by direct experimental evidence in human
      and orthologs.
    action: ACCEPT
    reason: IBA annotation consistent with experimental data. PIGS is an essential component
      of the GPI transamidase complex that attaches pre-assembled GPI anchors to the C-terminus
      of GPI-anchored proteins in the ER.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: The GPI transamidase mediates GPI anchoring in the endoplasmic reticulum,
        by replacing a protein's C-terminal GPI attachment signal peptide with a pre-assembled GPI.
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetically-inferred membership of the GPI-anchor transamidase complex. This
      is the core cellular component annotation for PIGS and is directly established by
      biochemistry and cryo-EM structures.
    action: ACCEPT
    reason: PIGS is one of the five subunits (PIGK, GPAA1, PIGT, PIGS, PIGU) of the GPI-T complex.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: 'Here, we report two new components of this enzyme: PIG-S and PIG-T.'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation to ER membrane from the UniProt Subcellular Location mapping.
      This is the correct and informative location for PIGS and is supported by experimental
      cryo-EM structural work.
    action: ACCEPT
    reason: PIGS is a multi-pass ER membrane protein, consistent with the ER-resident GPI-T complex.
    supported_by:
    - reference_id: file:human/PIGS/PIGS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation (combined IEA methods, via InterPro/ortholog) to attachment
      of GPI anchor to protein. Consistent with the experimentally established function.
    action: ACCEPT
    reason: Matches the well-supported core biological process; the InterPro PIG-S domain
      (IPR019540) is diagnostic of this family/function.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a
        complex with GAA1 and GPI8.
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Electronic annotation to GPI-anchor transamidase complex via combined IEA methods.
      Redundant with, and confirmed by, the experimental IDA/IBA complex annotations.
    action: ACCEPT
    reason: Correct complex membership, supported by biochemistry and structure.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: PIG-S and PIG-T form a protein complex with GAA1 and GPI8.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11483512
  qualifier: enables
  review:
    summary: Physical interaction (IPI) with PIGT (Q969N2). PIGT is a genuine partner within the
      GPI-T complex, so the interaction is biologically real, but the bare 'protein binding'
      term is uninformative and does not capture PIGS's role as a complex subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines, 'protein binding' (GO:0005515) is uninformative. The
      meaningful assertion (physical partnership with PIGT within GPI-T) is already captured by
      the GPI-anchor transamidase complex (GO:0042765) annotations. Retained but marked as
      over-annotated rather than removed, following policy on experimental IPIs.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: PIG-S and PIG-T form a protein complex with GAA1 and GPI8.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12802054
  qualifier: enables
  review:
    summary: Physical interaction (IPI) with PIGT (Q969N2) reported in the study that identified
      PIG-U as the fifth GPI-T subunit. Real interaction within GPI-T, but the generic term is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Bare protein binding is uninformative; the underlying biology (subunit of GPI-T) is
      captured by GO:0042765. Marked as over-annotated per policy rather than removed.'
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: The mammalian GPI transamidase is a complex of at least four subunits,
        GPI8, GAA1, PIG-S, and PIG-T.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Interactions reported from a proteome-scale (Y2H) binary interactome map. Partners
      here include keratin-associated proteins (P60410/KRTAP10-8, Q6A162/KRT40, Q7Z3S9/NOTCH2NLA),
      which are unlikely to be biologically meaningful GPI-T partners and are characteristic
      sticky/false-positive hits of large-scale binary screens.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Uninformative protein binding from a high-throughput interactome; partners are not
      established GPI-T components. Retained but marked over-annotated per policy on high-throughput
      IPIs.'
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: binary protein-protein interactions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Interactions from a reference binary human interactome map (HuRI). Includes PIGT
      (Q969N2), TRIP6 (Q15654) and multiple keratin-associated/NOTCH2NL proteins; only PIGT is a
      bona fide GPI-T partner.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Generic protein binding from a large-scale binary interactome; mostly non-physiological
      partners. Marked over-annotated per policy.'
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Interaction with PIGT (Q969N2) from an AP-MS proteome-scale interactome (BioPlex).
      The PIGT interaction is consistent with GPI-T membership, but the generic term is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Uninformative protein binding; the meaningful PIGT partnership is captured by the
      GPI-T complex annotation. Marked over-annotated per policy.'
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: cell-specific remodeling of the human interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Interaction with PIGT (Q969N2) from a multimodal (AP-MS/imaging) cell-map interactome
      study. Consistent with GPI-T assembly but reported as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Uninformative protein binding; underlying biology captured by GPI-T complex membership.
      Marked over-annotated per policy.'
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional genomics.
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: Electronic annotation to GPI anchor biosynthetic process via UniPathway mapping
      (UPA00196). PIGS participates in the terminal (transamidation) step of GPI-anchor
      biosynthesis and this broader parent process is appropriate.
    action: ACCEPT
    reason: Correct pathway-level BP; PIGS's UniProt PATHWAY is glycolipid biosynthesis;
      glycosylphosphatidylinositol-anchor biosynthesis.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: covalent attachment of GPI at the new carboxyl terminus are catalyzed by
        an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among all
        eukaryotes
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:12802054
  qualifier: located_in
  review:
    summary: Non-traceable-author-statement ER membrane localization (ComplexPortal, based on the
      GPI-T complex). Correct and now confirmed by structural studies.
    action: ACCEPT
    reason: ER membrane is the established, informative location for the GPI-T complex.
    supported_by:
    - reference_id: PMID:12582175
      supporting_text: GPI transamidase is localized in the endoplasmic reticulum and mediates
        post-translational transfer of preformed GPI to proteins bearing a carboxyl-terminal GPI
        attachment signal.
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: NAS
  original_reference_id: PMID:12802054
  qualifier: involved_in
  review:
    summary: NAS annotation (ComplexPortal) to attachment of GPI anchor to protein. Correct core
      biological process for the GPI-T complex.
    action: ACCEPT
    reason: The GPI-T complex, of which PIGS is a subunit, attaches GPI anchors to proteins.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: attaches GPI-anchors to proteins
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IPI
  original_reference_id: PMID:12802054
  qualifier: part_of
  review:
    summary: Physical-interaction-based (ComplexPortal) membership of the GPI-anchor transamidase
      complex. Directly supported by affinity purification identifying PIG-S among the complex
      components.
    action: ACCEPT
    reason: PIG-S co-purifies as a component of the affinity-purified GPI transamidase complex.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: The GPI transamidase complex affinity-purified from cells expressing
        epitope-tagged-GPI8 contained PIG-U and four other known components.
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: involved_in
  review:
    summary: Direct assay (cryo-EM structure of the human GPI-T complex) supporting PIGS's
      involvement in GPI-anchored protein biosynthesis. The structure defines the assembly and
      the substrate-binding cleft of the ER GPI-T complex.
    action: ACCEPT
    reason: Structural evidence directly supports PIGS as part of the machinery for GPI-AP
      biosynthesis.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: Attaching GPI to the protein in the endoplasmic reticulum (ER) is catalyzed
        by the transmembrane GPI transamidase (GPIT) complex, which is essential for maturation of
        the GPI-anchored proteins.
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:35551457
  qualifier: involved_in
  review:
    summary: Direct assay (cryo-EM structure of human GPI-T) supporting involvement in
      GPI-anchored protein biosynthesis. Reveals the equimolar heteropentameric assembly including
      PIGS.
    action: ACCEPT
    reason: Structural evidence directly supports PIGS's role in GPI-AP biogenesis.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: revealing an equimolar heteropentameric assembly
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:11483512
  qualifier: involved_in
  review:
    summary: Direct evidence from gene-disruption experiments (PIG-S knockout cells defective in
      GPI transfer) supporting involvement in GPI-anchored protein biosynthesis.
    action: ACCEPT
    reason: Knockout of PIG-S impairs transfer of GPI to proteins, demonstrating its role in
      GPI-AP biosynthesis.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: PIG-S and PIG-T knockout cells were defective in transfer of GPI to
        proteins, particularly in formation of the carbonyl intermediates.
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:30269814
  qualifier: involved_in
  review:
    summary: Direct evidence from patient/cell studies (GPIBD18) showing PIGS loss of function
      produces a GPI-AP deficiency profile, supporting its role in GPI-anchored protein
      biosynthesis.
    action: ACCEPT
    reason: Human loss-of-function causes GPI-AP deficiency, directly implicating PIGS in GPI-AP
      biosynthesis.
    supported_by:
    - reference_id: PMID:30269814
      supporting_text: Flow-cytometry analyses demonstrated that the individuals with PIGS
        mutations show a GPI-AP deficiency profile.
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:34576938
  qualifier: involved_in
  review:
    summary: Direct functional assay (rescue of GPI-AP surface expression in PIGS-KO cells)
      supporting PIGS's role in GPI-anchored protein biosynthesis; PIGS is indispensable for
      GPI-T activity.
    action: ACCEPT
    reason: Functional complementation in PIGS-KO cells directly supports involvement in GPI-AP
      biosynthesis.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: PIGS is an indispensable subunit of GPI-TA activity, although its role is
        unclear.
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:12802054
  qualifier: involved_in
  review:
    summary: Direct evidence (affinity purification / in vitro transamidase assays with the
      five-subunit complex) supporting PIGS's involvement in attachment of GPI anchor to protein.
    action: ACCEPT
    reason: The affinity-purified complex containing PIG-S mediates GPI attachment; loss of
      subunits abolishes transamidase activity.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: attaches GPI-anchors to proteins
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:34576938
  qualifier: involved_in
  review:
    summary: Direct functional assay supporting involvement in attachment of GPI anchor to protein;
      PIGS is required for GPI-T activity (loss of any subunit abolishes activity).
    action: ACCEPT
    reason: Mutagenesis/complementation confirms PIGS is required for GPI attachment activity.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: Attachment of GPI to proteins is mediated by the GPI-transamidase (GPI-TA)
        complex, which recognizes and cleaves the C-terminal GPI attachment signal of precursor
        proteins.
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: involved_in
  review:
    summary: Direct evidence from liganded (substrate/product-bound) cryo-EM structures of human
      GPI-T illuminating the transamidation/GPI-attachment mechanism.
    action: ACCEPT
    reason: Substrate- and product-bound structures directly define the GPI-attachment reaction of
      the complex containing PIGS.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: The transmembrane complex GPI-T recognizes diverse proproteins at a signal
        peptide region that lacks consensus sequence and replaces it with GPI via a transamidation
        reaction.
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: part_of
  review:
    summary: Direct structural evidence (liganded cryo-EM structures, PDB 8IMX/8IMY) for PIGS as a
      subunit of the GPI-anchor transamidase complex.
    action: ACCEPT
    reason: PIGS is resolved as a subunit in the cryo-EM structures of the human GPI-T complex.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: substrates- and products-bound human GPI-T structures
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: involved_in
  review:
    summary: Direct evidence (cryo-EM structure) supporting involvement in attachment of GPI
      anchor to protein; the structure identifies the catalytic triad and GPI substrate-binding
      cleft of the complex.
    action: ACCEPT
    reason: Structural work directly supports the GPI-attachment function of the complex containing
      PIGS.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: Attaching GPI to the protein in the endoplasmic reticulum (ER) is catalyzed
        by the transmembrane GPI transamidase (GPIT) complex
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:35551457
  qualifier: involved_in
  review:
    summary: Direct evidence (cryo-EM structure) supporting involvement in attachment of GPI
      anchor to protein; structure-based mutagenesis supports the transamidation mechanism.
    action: ACCEPT
    reason: Structural evidence directly supports the GPI-attachment function of the GPI-T complex
      that includes PIGS.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: The removal of a hydrophobic signal peptide and covalent attachment of GPI
        at the new carboxyl terminus are catalyzed by an endoplasmic reticulum membrane GPI
        transamidase complex (GPI-T)
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: part_of
  review:
    summary: Direct structural evidence (cryo-EM, PDB 7W72) for PIGS as one of the five subunits
      of the GPI-anchor transamidase complex.
    action: ACCEPT
    reason: PIGS is resolved as a subunit of the human GPI-T complex in the cryo-EM structure.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: 'The GPIT complex is known to be composed of five subunits: PIGK, PIGU,
        PIGT, PIGS and GPAA1.'
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:35551457
  qualifier: part_of
  review:
    summary: Direct structural evidence (cryo-EM) for PIGS as a subunit of the equimolar
      heteropentameric GPI-anchor transamidase complex.
    action: ACCEPT
    reason: PIGS is a subunit of the human GPI-T heteropentamer.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: revealing an equimolar heteropentameric assembly
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:12582175
  qualifier: part_of
  review:
    summary: Direct evidence for PIGS as part of the multimeric GPI transamidase complex; this
      study on the GPI8-PIG-T disulfide bridge confirms an inactive five-component complex holds
      the substrate protein.
    action: ACCEPT
    reason: Biochemistry places PIG-S among the five components of the mammalian GPI transamidase
      complex.
    supported_by:
    - reference_id: PMID:12582175
      supporting_text: an inactive human GPI transamidase complex that consists of non-functional
        GPI8 and four other components
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:34576938
  qualifier: part_of
  review:
    summary: Direct evidence (co-purification of all five subunits confirmed by mass spectrometry)
      for PIGS as a subunit of the GPI-anchor transamidase complex.
    action: ACCEPT
    reason: All five GPI-TA subunits, including PIGS, co-purify as the assembled complex.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: 'GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU, and
        the absence of any subunit leads to the loss of activity.'
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:12802054
  qualifier: part_of
  review:
    summary: Direct evidence (affinity purification of the complex) for PIGS as a component of the
      GPI-anchor transamidase complex.
    action: ACCEPT
    reason: PIG-S is a component of the affinity-purified GPI transamidase complex.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: The GPI transamidase complex affinity-purified from cells expressing
        epitope-tagged-GPI8 contained PIG-U and four other known components.
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:11483512
  qualifier: part_of
  review:
    summary: Direct evidence for PIG-S as a component of the GPI transamidase complex, forming a
      complex with GAA1, GPI8 (PIGK) and PIG-T.
    action: ACCEPT
    reason: Foundational biochemical identification of PIG-S as a GPI-T subunit.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: PIG-S and PIG-T form a protein complex with GAA1 and GPI8.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput proteomics detected PIGS in the membrane proteome of an NK-like cell
      line. This localizes PIGS to a membrane but is far less informative than the established ER
      membrane annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'GO:0016020 (membrane) is a correct but unspecific parent; the informative location is
      endoplasmic reticulum membrane (GO:0005789). Retained but marked as over-annotated.'
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: define the composition of the membrane proteome of the Natural Killer (NK)
        like cell line YTS
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162836
  qualifier: located_in
  review:
    summary: Traceable-author-statement (Reactome) localization to the ER membrane, in the context
      of GPI-anchor attachment reactions. Correct and consistent with all other evidence.
    action: ACCEPT
    reason: ER membrane is the established location of the GPI-T complex.
    supported_by:
    - reference_id: file:human/PIGS/PIGS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: TAS
  original_reference_id: PMID:11483512
  qualifier: involved_in
  review:
    summary: Traceable-author-statement to attachment of GPI anchor to protein, from the paper
      identifying PIG-S as essential for GPI anchor attachment.
    action: ACCEPT
    reason: Core, well-supported biological process for PIGS.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a
        complex with GAA1 and GPI8.
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: TAS
  original_reference_id: PMID:15713669
  qualifier: part_of
  review:
    summary: Traceable-author-statement for PIGS as one of the five subunits of the ER-localized
      GPI transamidase complex.
    action: ACCEPT
    reason: Consistent with the established five-subunit GPI-T complex membership.
    supported_by:
    - reference_id: PMID:15713669
      supporting_text: two of the five subunits of the ER-localized glycosylphosphatidylinositol
        transamidase complex
core_functions:
- description: PIGS is a required, non-catalytic subunit of the ER membrane GPI-anchor
    transamidase (GPI-T) complex, which post-translationally attaches a pre-assembled GPI anchor
    to the C-terminus of GPI-anchored proteins, replacing their C-terminal GPI-attachment signal
    peptide. PIGS is indispensable for complex activity but does not itself catalyze the reaction
    (PIGK is catalytic; GPAA1 forms the amide bond).
  directly_involved_in:
  - id: GO:0016255
    label: attachment of GPI anchor to protein
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  supported_by:
  - reference_id: PMID:11483512
    supporting_text: PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a
      complex with GAA1 and GPI8.
  - reference_id: PMID:34576938
    supporting_text: PIGS is an indispensable subunit of GPI-TA activity, although its role is
      unclear.
  - reference_id: PMID:35551457
    supporting_text: The removal of a hydrophobic signal peptide and covalent attachment of GPI at
      the new carboxyl terminus are catalyzed by an endoplasmic reticulum membrane GPI transamidase
      complex (GPI-T)
proposed_new_terms: []
suggested_questions:
- question: What is the specific molecular role of PIGS within the GPI-T complex (e.g. substrate
    proprotein recognition, lumenal-domain scaffolding, or stabilization of catalytic subunits),
    given that it is indispensable for activity yet non-catalytic?
  experts:
  - Taroh Kinoshita
suggested_experiments:
- description: Structure-guided mutagenesis of the PIGS lumenal domain interface with PIGK/GPAA1
    combined with in vitro transamidase and cell-surface GPI-AP rescue assays to define which
    PIGS surfaces are required for substrate handling versus complex assembly.
  hypothesis: PIGS contributes to substrate proprotein recognition and/or stabilization of the
    catalytic subunits rather than to catalysis itself.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/PIGS/PIGS-uniprot.txt
  title: UniProtKB entry Q96S52 (PIGS_HUMAN), GPI-anchor transamidase component PIGS
  findings: []
- id: PMID:11483512
  title: PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a
    complex with GAA1 and GPI8.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational paper identifying PIG-S as an essential GPI transamidase
      subunit forming a complex with GAA1, GPI8 (PIGK) and PIG-T; abstract directly supports
      complex membership and function.
- id: PMID:12582175
  title: Two subunits of glycosylphosphatidylinositol transamidase, GPI8 and PIG-T,
    form a functionally important intermolecular disulfide bridge.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Focus is the GPI8-PIG-T disulfide bond, but the abstract confirms the
      five-component mammalian GPI transamidase complex that includes PIG-S; supports complex
      membership.
- id: PMID:12802054
  title: Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that
    attaches GPI-anchors to proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Identifies PIG-U as the fifth subunit; affinity-purified complex includes
      PIG-S; supports complex membership and GPI-attachment function.
- id: PMID:15713669
  title: Endoplasmic reticulum localization of Gaa1 and PIG-T, subunits of the glycosylphosphatidylinositol
    transamidase complex.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes ER localization of GPI-T subunits and references the five-subunit
      ER-localized complex that includes PIG-S.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput membrane proteomics of an NK-like cell line; supports only a
      generic membrane localization for PIGS.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale binary interactome; PIGS interactions here are mostly
      non-physiological (keratin-associated proteins) and support only generic protein binding.
- id: PMID:30269814
  title: Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome
    Ranging from Fetal Akinesia to Epileptic Encephalopathy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines GPIBD18; biallelic PIGS loss-of-function causes GPI-AP deficiency,
      directly linking PIGS to GPI-AP biosynthesis.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI binary interactome; only the PIGT interaction is a bona fide GPI-T partner,
      the rest support only generic protein binding.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex AP-MS; PIGT interaction consistent with GPI-T membership but recorded as
      generic protein binding.
- id: PMID:34576938
  title: Functional Analysis of the GPI Transamidase Complex by Screening for Amino
    Acid Mutations in Each Subunit.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; states GPI-TA has five subunits, that PIGS is indispensable
      for activity, and characterizes functionally important residues; supports complex membership
      and requirement.
- id: PMID:35165458
  title: Structure of human glycosylphosphatidylinositol transamidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cryo-EM structure of human GPI-T (PDB 7W72); PIGS resolved as one of five
      subunits; identifies PIGK catalytic triad and substrate-binding cleft.
- id: PMID:35551457
  title: Molecular insights into biogenesis of glycosylphosphatidylinositol anchor
    proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cryo-EM structure showing equimolar heteropentameric GPI-T assembly
      including PIGS; ER membrane localization confirmed.
- id: PMID:37684232
  title: Structures of liganded glycosylphosphatidylinositol transamidase illuminate
    GPI-AP biogenesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Substrate/product-bound cryo-EM structures (PDB 8IMX/8IMY) of human GPI-T
      including PIGS; illuminates the transamidation mechanism.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; PIGT interaction consistent with GPI-T, but
      recorded as generic protein binding.
- id: Reactome:R-HSA-162836
  title: uPAR precursor + acyl-GPI -> uPAR-acyl-GPI + uPAR propeptide
  findings: []