id: O43292
gene_symbol: GPAA1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GPAA1 (GAA1; glycosylphosphatidylinositol anchor attachment 1 protein) is a
  multi-pass endoplasmic reticulum membrane protein and one of the five subunits
  of the GPI-anchor transamidase (GPI-T) complex (with PIGK, PIGT, PIGS and PIGU).
  This complex catalyses the last step of GPI-anchored protein biosynthesis:
  in the ER lumen it removes the C-terminal GPI-attachment signal peptide of
  precursor proteins and, through a transamidation reaction, replaces it with a
  pre-assembled GPI anchor at the new C-terminus. The catalytic cysteine-protease
  chemistry that cleaves the signal peptide and forms the acyl(carbonyl)-enzyme
  intermediate resides in the PIGK subunit; GPAA1, which adopts an M28
  peptidase-like fold, is a required accessory subunit that binds the GPI lipid
  substrate and coordinates its three ethanolamine-phosphate arms, positioning
  the bridging ethanolamine-phosphate for amide-bond formation with the substrate
  omega-site. GPAA1 is passively retained in the ER, and its large luminal loop
  mediates assembly with the other subunits. Biallelic loss-of-function variants
  in GPAA1 cause an inherited GPI-deficiency disorder (GPI biosynthesis defect 15;
  GPIBD15) presenting with developmental delay, hypotonia, early-onset seizures,
  cerebellar atrophy and osteopenia, and reduced cell-surface levels of
  GPI-anchored proteins.
alternative_products:
- name: '1'
  id: O43292-1
- name: '2'
  id: O43292-2
  sequence_note: VSP_009542
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 core biological process. GPAA1 orthologs across
      eukaryotes (yeast Gaa1p, Drosophila) are components of the GPI transamidase
      that attaches GPI to precursor proteins. Well supported by direct
      experimental evidence in human (see IDA/EXP annotations).
    action: ACCEPT
    reason: >-
      Correct, appropriately specific core BP; matches direct experimental
      annotations and the phylogenetic consensus.
    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 complex membership. GPAA1 is a conserved subunit
      of the GPI-anchor transamidase complex; this is confirmed by direct
      co-purification, mutagenesis and cryo-EM structures of the human complex.
    action: ACCEPT
    reason: >-
      Core, correct complex-membership assignment consistent with experimental
      evidence.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation from the UniProt subcellular-location vocabulary.
      GPAA1 is a multi-pass ER membrane protein; supported directly by
      experimental localization studies.
    action: ACCEPT
    reason: >-
      Correct core localization; consistent with experimental and structural
      evidence that GPAA1 is a multi-pass ER membrane protein.
    supported_by:
    - reference_id: file:human/GPAA1/GPAA1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro2GO electronic annotation to the generic 'membrane' term. True but
      uninformative: the specific and correct location is the ER membrane
      (GO:0005789), which is separately annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant, low-information parent of the more specific ER membrane
      annotation; retained but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/GPAA1/GPAA1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: >-
      InterPro2GO electronic annotation (IPR007246, Gaa1) to the transamidase
      complex. Correct complex membership, confirmed experimentally.
    action: ACCEPT
    reason: >-
      Correct core complex-membership term; consistent with experimental and
      structural data.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10793132
  qualifier: enables
  review:
    summary: >-
      IntAct/UniProt binary interaction with PIGK (Q92643), the catalytic
      subunit of the same complex. The interaction is real but the bare
      'protein binding' term is uninformative; the biologically meaningful
      relationship is captured by GPI-anchor transamidase complex membership.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-informative molecular-function term (bare protein binding); the
      underlying PIGK interaction is already represented by complex membership.
      Per curation policy this IPI is not removed.
    supported_by:
    - reference_id: PMID:10793132
      supporting_text: >-
        Gaa1p and Gpi8p are associated with each other.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11483512
  qualifier: enables
  review:
    summary: >-
      IntAct/UniProt interaction (with PIGK Q92643) supporting GPI-T complex
      assembly. Bare 'protein binding' is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-informative MF term; the relevant biology (co-complex with the other
      GPI-T subunits) is captured by GO:0042765. Not removed per policy.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: >-
        PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12802054
  qualifier: enables
  review:
    summary: >-
      IntAct/UniProt interaction (with PIGK Q92643) within the GPI transamidase
      complex, which PMID:12802054 shows is a five-subunit assembly. Bare
      'protein binding' is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-informative MF term; complex membership is the meaningful annotation.
      Not removed per policy.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        The mammalian GPI transamidase is a
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      High-throughput AP-MS interactome (BioPlex 2.0) binary interactions
      (PIGK Q92643, PIGT Q969N2, MOXD1 Q6UVY6). Bare 'protein binding' is
      uninformative and derives from a proteome-scale screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-informative MF term from a large-scale interactome study; complex
      membership already captures the relevant partners. Not removed per policy.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: >-
        the largest such network so far
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      High-throughput AP-MS interactome (BioPlex 3.0) interactions. Bare
      'protein binding' is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-informative MF term from a proteome-scale interactome; not removed per
      policy.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: >-
        we have created two proteome-scale, cell-line-specific
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      High-throughput multimodal cell-map interactome (PIGK Q92643, PIGT
      Q969N2). Bare 'protein binding' is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-informative MF term from a proteome-scale mapping study; not removed
      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: >-
      UniPathway-based electronic annotation to the parent GPI-anchor
      biosynthesis process. GPAA1 acts in the terminal transamidation step of
      this pathway.
    action: ACCEPT
    reason: >-
      Correct parent BP for GPAA1's role in GPI-anchored protein biosynthesis.
    supported_by:
    - reference_id: file:human/GPAA1/GPAA1-uniprot.txt
      supporting_text: >-
        PATHWAY: Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor
        biosynthesis.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:12802054
  qualifier: located_in
  review:
    summary: >-
      ComplexPortal (NAS) assignment of the GPI-anchor transamidase complex to
      the ER membrane. Consistent with direct experimental localization of GPAA1.
    action: ACCEPT
    reason: >-
      Correct core localization; corroborated by experimental evidence.
    supported_by:
    - reference_id: PMID:12582175
      supporting_text: >-
        GPI transamidase is localized in the
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: NAS
  original_reference_id: PMID:12802054
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal (NAS) assignment of the transamidase complex process to
      GPAA1. Correct core BP, confirmed by experimental data.
    action: ACCEPT
    reason: >-
      Correct core BP; consistent with the direct experimental annotations.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        GPI transamidase that 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: >-
      Affinity-purification evidence that GPAA1 is part of the GPI transamidase
      complex; this paper established PIG-U as the fifth subunit alongside GAA1,
      GPI8, PIG-S and PIG-T.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation, experimentally supported.
    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:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Human Protein Atlas immunofluorescence localizes GPAA1 to the endoplasmic
      reticulum. Consistent with its role as an ER-membrane transamidase subunit;
      the ER membrane (GO:0005789) is the more precise location.
    action: ACCEPT
    reason: >-
      Correct localization to the ER (parent of ER membrane); consistent with all
      other localization data.
    supported_by:
    - reference_id: file:human/GPAA1/GPAA1-uniprot.txt
      supporting_text: >-
        GO:0005783; C:endoplasmic reticulum; IDA:HPA.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:11483512
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of the GAA1-containing transamidase to the ER
      membrane, where it mediates GPI anchoring.
    action: ACCEPT
    reason: >-
      Correct core localization, directly supported.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: >-
        The GPI transamidase mediates GPI anchoring in the endoplasmic
        reticulum
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: involved_in
  review:
    summary: >-
      Cryo-EM structure of the human GPI transamidase (PIGK/PIGU/PIGT/PIGS/GPAA1)
      demonstrating its role in maturation of GPI-anchored proteins.
    action: ACCEPT
    reason: >-
      Correct core BP, directly supported by the structural characterization of
      the complex containing GPAA1.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: >-
        composed of five subunits: PIGK, PIGU, PIGT, PIGS and GPAA1
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:35551457
  qualifier: involved_in
  review:
    summary: >-
      Cryo-EM structure of the human GPI-T heteropentamer including GPAA1,
      illuminating GPI-anchored protein biogenesis.
    action: ACCEPT
    reason: >-
      Correct core BP; directly supported by structural data on the GPAA1-
      containing complex.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        GPI-T at a global 2.53-Å resolution, revealing an equimolar
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:29100095
  qualifier: involved_in
  review:
    summary: >-
      Functional evidence that GPAA1 is essential for attaching GPI to precursor
      proteins: patient cells with biallelic GPAA1 variants show reduced surface
      levels of GPI-anchored proteins.
    action: ACCEPT
    reason: >-
      Correct core BP, supported by loss-of-function disease evidence.
    supported_by:
    - reference_id: PMID:29100095
      supporting_text: >-
        This complex orchestrates the attachment of the GPI anchor to the
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:9468317
  qualifier: involved_in
  review:
    summary: >-
      Original cloning of human GAA1; antisense knockdown reduced production of a
      reporter GPI-anchored protein, implicating GPAA1 in GPI attachment.
    action: ACCEPT
    reason: >-
      Correct core BP; supported by functional knockdown evidence.
    supported_by:
    - reference_id: PMID:9468317
      supporting_text: >-
        Overexpression of antisense hGAA1 in human K562 cells significantly
        reduced the production of a reporter GPI-anchored protein
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:9468317
  qualifier: part_of
  review:
    summary: >-
      GPAA1 identified as a component of the putative transamidase machinery.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation.
    supported_by:
    - reference_id: PMID:9468317
      supporting_text: >-
        We have isolated a component of the putative transamidase
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:29100095
  qualifier: involved_in
  review:
    summary: >-
      GPAA1 as an essential component of the transamidase complex in GPI-anchored
      protein biosynthesis; loss of function reduces surface GPI-APs.
    action: ACCEPT
    reason: >-
      Correct core BP, supported by disease/functional evidence.
    supported_by:
    - reference_id: PMID:29100095
      supporting_text: >-
        GPI-anchored proteins had decreased cell-surface abundance in
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:34576938
  qualifier: involved_in
  review:
    summary: >-
      Mutational screen of GPI-TA subunits confirming GPAA1 function in GPI
      anchoring (GPAA1 D250A reduces activity).
    action: ACCEPT
    reason: >-
      Correct core BP, directly supported by functional mutagenesis.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        The D250A construct reduced GPI-TA activity without changing the protein
        stability
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: involved_in
  review:
    summary: >-
      Liganded GPI-T structures showing GPAA1 within the complex engaged in
      GPI-anchored protein biogenesis (GPI substrate bound).
    action: ACCEPT
    reason: >-
      Correct core BP, directly supported by structural data on the substrate-
      and product-bound complex.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: >-
        EtNP2 is fixed by GPAA1 Gln355 and Ser51
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:9468317
  qualifier: involved_in
  review:
    summary: >-
      GPAA1 functionally implicated in production of GPI-anchored proteins via
      antisense knockdown.
    action: ACCEPT
    reason: >-
      Correct core BP; functional knockdown evidence.
    supported_by:
    - reference_id: PMID:9468317
      supporting_text: >-
        Overexpression of antisense hGAA1 in human K562 cells significantly
        reduced the production of a reporter GPI-anchored protein
- term:
    id: GO:0034235
    label: GPI anchor binding
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: enables
  review:
    summary: >-
      Liganded cryo-EM structures directly show GPAA1 binding the GPI lipid
      substrate: GPAA1 residues coordinate the three ethanolamine-phosphate arms
      of GPI (EtNP1-His354 via Mg2+, EtNP2-Gln355/Ser51, EtNP3-Ser51/Asn53).
      This is GPAA1's specific molecular function within the complex.
    action: ACCEPT
    reason: >-
      Well-supported, informative core molecular function (GPI lipid-substrate
      binding), established by liganded structures.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: >-
        EtNP1 interacts with GPAA1 His354 through metal coordination (modeled as
        Mg2+)
    - reference_id: PMID:37684232
      supporting_text: >-
        Finally, EtNP3 interacts with GPAA1 Ser51 and Asn53
- 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 for the transamidase complex (containing GAA1) attaching
      GPI anchors to proteins.
    action: ACCEPT
    reason: >-
      Correct core BP, experimentally supported.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        GPI transamidase that 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: >-
      Functional analysis of GPI-TA subunits including GPAA1, confirming its role
      in GPI attachment; GPAA1 is proposed to catalyse formation of the amide
      bond between the substrate omega-site and the bridging EtNP.
    action: ACCEPT
    reason: >-
      Correct core BP, supported by mutagenesis and functional rescue assays.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        GPAA1 is proposed to catalyze the formation of an amide bond between the
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: involved_in
  review:
    summary: >-
      Substrate/product-bound GPI-T structures directly visualise the attachment
      reaction, with GPAA1 binding the GPI substrate.
    action: ACCEPT
    reason: >-
      Correct core BP, directly supported by structural data.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: >-
        EtNP2 is fixed by GPAA1 Gln355 and Ser51
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: part_of
  review:
    summary: >-
      Cryo-EM structures of the GPI-T complex including GPAA1 (light blue subunit)
      with PIGK, PIGT, PIGS and PIGU.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation, structurally confirmed.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: >-
        a Interactions between the product ULBP2* and GPI-T (GPAA1, light blue;
        PIGK, marine blue; PIGT, purple; PGIS, cyan).
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: involved_in
  review:
    summary: >-
      Cryo-EM structure of the human GPI transamidase catalysing GPI attachment
      to proteins in the ER.
    action: ACCEPT
    reason: >-
      Correct core BP, structurally supported.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: >-
        composed of five subunits: PIGK, PIGU, PIGT, PIGS and GPAA1
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:35551457
  qualifier: involved_in
  review:
    summary: >-
      Cryo-EM structure of the human GPI-T heteropentamer engaged in the removal
      of the signal peptide and covalent attachment of GPI.
    action: ACCEPT
    reason: >-
      Correct core BP, structurally supported.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        covalent attachment of GPI at the new carboxyl terminus
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: part_of
  review:
    summary: >-
      Cryo-EM structure demonstrating GPAA1 as one of the five subunits of the
      human GPI transamidase complex.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation, structurally confirmed.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: >-
        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: >-
      Cryo-EM structure of the equimolar heteropentameric GPI-T complex including
      GPAA1.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation, structurally confirmed.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        GPI-T at a global 2.53-Å resolution, revealing an equimolar
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:12582175
  qualifier: part_of
  review:
    summary: >-
      Biochemical evidence that the human GPI transamidase is a multimeric complex
      of five components (including GAA1) sufficient to hold the substrate protein.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation.
    supported_by:
    - reference_id: PMID:12582175
      supporting_text: >-
        indicating that these five components are sufficient to
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:34576938
  qualifier: part_of
  review:
    summary: >-
      Purified human GPI-TA containing GPAA1 with the four other subunits.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation, experimentally supported.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IMP
  original_reference_id: PMID:14660601
  qualifier: involved_in
  review:
    summary: >-
      Mutation of a conserved proline in the last TM segment of GAA1 abolishes
      GPI recognition/binding by the transamidase, impairing GPI attachment.
    action: ACCEPT
    reason: >-
      Correct core BP, supported by mutational (IMP) evidence linking GAA1 to
      the attachment reaction.
    supported_by:
    - reference_id: PMID:14660601
      supporting_text: >-
        required for glycosylphosphatidylinositol (GPI) recognition by GPI
        transamidase
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:12802054
  qualifier: part_of
  review:
    summary: >-
      Affinity-purified GPI transamidase complex containing GAA1 and the four
      other subunits.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation.
    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: >-
      GAA1 shown to form a protein complex with GPI8, PIG-S and PIG-T.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation, experimentally supported.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: >-
        PIG-S and PIG-T form a protein complex with GAA1 and GPI8
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:14660601
  qualifier: part_of
  review:
    summary: >-
      GAA1 shown to be part of the multisubunit human GPI transamidase (Gaa1,
      Gpi8, PIG-S, PIG-T, PIG-U).
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation.
    supported_by:
    - reference_id: PMID:14660601
      supporting_text: >-
        Human GPIT is a multisubunit membrane-bound protein complex
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry identification of GPAA1 in an NK-cell
      membrane proteome. Generic 'membrane' term; the specific location is the
      ER membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative parent term from a proteome-scale membrane fractionation;
      the specific ER membrane location is annotated separately.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        define the composition of the membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162836
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assignment of GPAA1 (as part of the GPI transamidase
      reaction) to the ER membrane.
    action: ACCEPT
    reason: >-
      Correct core localization, consistent with all other evidence.
    supported_by:
    - reference_id: file:human/GPAA1/GPAA1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- term:
    id: GO:0034235
    label: GPI anchor binding
  evidence_type: IMP
  original_reference_id: PMID:14660601
  qualifier: contributes_to
  review:
    summary: >-
      Truncation of GAA1's C-terminal TM span, or mutation of a conserved proline
      within it, prevents the transamidase complex from co-immunoprecipitating
      GPI while leaving assembly intact - showing GAA1 contributes to GPI binding
      by the complex.
    action: ACCEPT
    reason: >-
      Correct, informative core molecular function; the contributes_to qualifier
      appropriately captures that GPI binding is a property of the complex to
      which GAA1 contributes.
    supported_by:
    - reference_id: PMID:14660601
      supporting_text: >-
        abrogate the ability of the resulting GPIT complex to co-immunoprecipitate
        GPI
- term:
    id: GO:0006621
    label: protein retention in ER lumen
  evidence_type: NAS
  original_reference_id: PMID:12052837
  qualifier: involved_in
  review:
    summary: >-
      The cited paper describes how GAA1 itself is retained in the ER (a
      signalless, passive mechanism) and how its cytoplasmic N terminus may act
      as a membrane-sorting determinant for GAA1 and associated GPIT subunits.
      It does not show that GPAA1 retains other proteins in the ER lumen, and
      GPAA1 is not a KDEL-receptor-type lumenal-retention factor. The GO term
      'protein retention in ER lumen' is therefore a poor fit for GPAA1's biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Term/paper mismatch: PMID:12052837 concerns retention of GAA1 (and its own
      complex) in the ER membrane, not retention of substrate proteins in the ER
      lumen. NAS evidence; not experimentally supported for this process.
    supported_by:
    - reference_id: PMID:12052837
      supporting_text: >-
        the cytoplasmic N terminus of Gaa1 is not required for formation of a
        functional GPIT complex but may act as a membrane-sorting determinant
        directing Gaa1 and associated GPIT subunits to an endoplasmic reticulum
        membrane domain.
- 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 assertion that the GAA1-containing transamidase attaches GPI to
      the C-terminus of precursor proteins in the ER.
    action: ACCEPT
    reason: >-
      Correct core BP, consistent with all experimental evidence.
    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:0016255
    label: attachment of GPI anchor to protein
  evidence_type: NAS
  original_reference_id: PMID:9468317
  qualifier: involved_in
  review:
    summary: >-
      Non-traceable assertion that human GAA1 is required for attachment of GPI
      to proteins (original cloning paper).
    action: ACCEPT
    reason: >-
      Correct core BP; corroborated by later direct experimental evidence.
    supported_by:
    - reference_id: PMID:9468317
      supporting_text: >-
        required for attachment of glycosylphosphatidylinositols to proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15713669
  qualifier: enables
  review:
    summary: >-
      IntAct/UniProt interaction (with PIGT Q969N2) within the ER-localized GPI
      transamidase complex. Bare 'protein binding' is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-informative MF term; the PIGT interaction is captured by complex
      membership (GO:0042765). Not removed per policy.
    supported_by:
    - reference_id: PMID:15713669
      supporting_text: >-
        human Gaa1 and PIG-T, two of the five subunits
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: TAS
  original_reference_id: PMID:15713669
  qualifier: part_of
  review:
    summary: >-
      Traceable assertion that GAA1 is one of the five subunits of the
      ER-localized GPI transamidase complex.
    action: ACCEPT
    reason: >-
      Correct core complex-membership annotation.
    supported_by:
    - reference_id: PMID:15713669
      supporting_text: >-
        human Gaa1 and PIG-T, two of the five subunits
core_functions:
- description: >-
    Binds the pre-assembled GPI lipid substrate as an accessory subunit of the
    ER-membrane GPI-anchor transamidase complex, coordinating the ethanolamine-
    phosphate arms of GPI (via residues including Ser51, His354 and Gln355) to
    position the bridging ethanolamine-phosphate for amide-bond formation during
    transfer of the GPI anchor to the substrate protein's C-terminal omega-site.
    Catalytic cleavage of the GPI-attachment signal peptide is performed by the
    PIGK subunit, not GPAA1.
  molecular_function:
    id: GO:0034235
    label: GPI anchor binding
  directly_involved_in:
  - 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
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: file:human/GPAA1/GPAA1-uniprot.txt
  title: UniProtKB entry O43292 (GPAA1_HUMAN)
  findings: []
- id: PMID:10793132
  title: Gaa1p and gpi8p are components of a glycosylphosphatidylinositol (GPI) transamidase
    that mediates attachment of GPI to proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes that GAA1 and GPI8 are the core transamidase components and that
      GPI8 (PIGK) is the catalytic cysteine-protease subunit; GAA1 KO abolishes
      carbonyl-intermediate formation. Abstract-only cache.
- 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: >-
      Defines the GAA1/GPI8/PIG-S/PIG-T complex and its ER localization; source of
      the direct protein-sequence and complex-assembly annotations. Abstract-only.
- id: PMID:12052837
  title: Structural requirements for the recruitment of Gaa1 into a functional glycosylphosphatidylinositol
    transamidase complex.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: MISCITED
    review_notes: >-
      Concerns ER retention/sorting of GAA1 itself and complex assembly via its
      luminal domain; does NOT support 'protein retention in ER lumen' (GO:0006621)
      as a GPAA1 function acting on other proteins - that annotation is a term/paper
      mismatch. Relevant for localization/assembly. Abstract-only.
- 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: >-
      GPI8-PIG-T disulfide bridge and confirmation the five-component complex holds
      substrate; supports complex membership. Abstract-only.
- 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: >-
      Establishes PIG-U as the fifth subunit alongside GAA1; affinity-purified
      complex; supports complex membership and attachment BP. Abstract-only.
- id: PMID:14660601
  title: A conserved proline in the last transmembrane segment of Gaa1 is required
    for glycosylphosphatidylinositol (GPI) recognition by GPI transamidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct functional link between GAA1 and GPI recognition/binding by the
      complex (co-IP of GPI abolished by GAA1 C-terminal TM mutation); basis of the
      GPI anchor binding (contributes_to) IMP annotation. Abstract-only.
- 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: >-
      Shows GAA1 is passively retained in the ER by a signalless mechanism;
      supports ER-membrane localization and complex membership. Abstract-only.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput membrane-proteome MS; only supports the generic 'membrane'
      HDA term, which is over-annotated relative to the specific ER membrane.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 2.0 proteome-scale AP-MS; source of bare 'protein binding' IPIs
      (PIGK/PIGT/MOXD1). Interactions plausible but term uninformative.
- id: PMID:29100095
  title: Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental
    Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines GPIBD15 disease; biallelic GPAA1 variants reduce surface GPI-APs;
      supports the attachment BP and disease context. Abstract-only.
- 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 3.0 proteome-scale AP-MS; bare 'protein binding' IPI source.
- 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 cached; systematic mutagenesis of all five subunits. Confirms PIGK
      is catalytic, GPAA1 has M28-peptidase-like fold, GPAA1 D250A reduces activity,
      and GPAA1 proposed to form the amide bond with the bridging EtNP.
- id: PMID:35165458
  title: Structure of human glycosylphosphatidylinositol transamidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cryo-EM structure of the human GPI-T; PIGK C206-H164-N58 catalytic triad;
      TM cleft as GPI substrate-binding site. Abstract-only cache.
- id: PMID:35551457
  title: Molecular insights into biogenesis of glycosylphosphatidylinositol anchor
    proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      2.53-Å cryo-EM structure of the equimolar heteropentameric GPI-T; legumain-
      like proprotein cleavage mechanism; GPAA1 His354 mutation reduces activity.
      Abstract-only cache.
- id: PMID:37684232
  title: Structures of liganded glycosylphosphatidylinositol transamidase illuminate
    GPI-AP biogenesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text cached; substrate/product-bound GPI-T structures. Directly shows
      GPAA1 binding the GPI lipid (EtNP1-His354/Mg2+, EtNP2-Gln355/Ser51,
      EtNP3-Ser51/Asn53); basis of the GPI anchor binding IDA and core MF.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale multimodal cell-map interactome; bare 'protein binding' IPI
      source (PIGK/PIGT).
- id: PMID:9468317
  title: Molecular cloning of human homolog of yeast GAA1 which is required for attachment
    of glycosylphosphatidylinositols to proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original cloning of human GAA1; antisense knockdown reduces reporter GPI-AP;
      basis of the attachment BP and complex-component annotations. Abstract-only.
- id: Reactome:R-HSA-162836
  title: uPAR precursor + acyl-GPI -> uPAR-acyl-GPI + uPAR propeptide
  findings: []