id: Q9UHJ9
gene_symbol: PGAP2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PGAP2 (Post-GPI Attachment to Proteins Factor 2; also FRAG1) is a multi-pass
  Golgi-membrane protein that carries out the second step of glycosylphosphatidylinositol
  (GPI) fatty-acid remodeling. GPI anchors are made in the endoplasmic reticulum and
  attached to nascent proteins, then remodeled during transport through the Golgi. In
  the Golgi, after PGAP3 removes the sn-2 unsaturated fatty acid, PGAP2 is required to
  reacylate the resulting lyso-GPI intermediate with a saturated (stearic) fatty acid
  at the sn-2 position; it is annotated as an acyltransferase (EC 2.3.-.-) by similarity,
  though whether it is the catalytic acyltransferase or an accessory factor required for
  reacylation is not firmly established. This fatty-acid remodeling generates the mature,
  detergent-resistant-membrane (lipid-raft)-associating GPI anchor and is required for
  stable cell-surface expression of GPI-anchored proteins such as DAF (CD55) and CD59.
  Biallelic hypomorphic PGAP2 variants cause hyperphosphatasia with impaired intellectual
  development syndrome 3 (HPMRS3), characterized by intellectual disability, hypotonia,
  and elevated serum alkaline phosphatase.
alternative_products:
- name: '2'
  id: Q9UHJ9-1
- name: '1'
  id: Q9UHJ9-2
  sequence_note: VSP_032550
- name: '3'
  id: Q9UHJ9-3
  sequence_note: VSP_032551
- name: '4'
  id: Q9UHJ9-4
  sequence_note: VSP_045984, VSP_045985
- name: '5'
  id: Q9UHJ9-5
  sequence_note: VSP_053800, VSP_032551
existing_annotations:
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PGAP2 acts in the GPI-anchor pathway, carrying out (or being required for)
      the second fatty-acid remodeling step in which a lyso-GPI intermediate is reacylated
      with a saturated stearoyl chain. This phylogenetically-inferred BP annotation is
      the core biological process for the gene and is well supported by experimental and
      by-similarity evidence.
    action: ACCEPT
    reason: Core biological process, concordant with experimental (IDA/IMP) annotations
      and the UniProt-curated function. The more specific child term GO:0120574 (GPI anchor
      remodelling) is also present and captured below.
    supported_by:
    - reference_id: PMID:29374258
      supporting_text: In the Golgi, GPI-APs undergo fatty acid remodeling where PGAP3
        removes an sn-2-linked unsaturated fatty acid and PGAP2 is involved in reacylation
        with stearic acid, a
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ER-membrane localization inferred from the phylogenetic tree. GPI-anchor
      biosynthesis begins in the ER, so ER association is plausible, but the experimentally
      supported and functionally relevant location for PGAP2's fatty-acid remodeling step
      is the Golgi. Retained as a non-core location.
    action: KEEP_AS_NON_CORE
    reason: Plausible given the ER-to-Golgi span of the GPI pathway, but the mature remodeling
      function and experimental localization are Golgi; ER membrane is not the core site
      of action.
    supported_by:
    - reference_id: file:human/PGAP2/PGAP2-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Golgi membrane localization derived from InterPro/UniProt automated pipelines.
      This is the core, experimentally supported location where PGAP2 performs GPI fatty-acid
      remodeling.
    action: ACCEPT
    reason: Correct core cellular component; concordant with the EXP annotation (PMID:10585768)
      and UniProt subcellular location.
    supported_by:
    - reference_id: file:human/PGAP2/PGAP2-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Binary protein-protein interaction (with KRTAP10-9, UniProtKB:P60411) recorded
      by a proteome-scale interactome screen. This uninformative protein-binding term
      does not convey PGAP2's molecular function and the partner is not part of the GPI
      remodeling machinery.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput binary interactome map is
      uninformative and does not describe PGAP2's function; retained per policy (do not
      REMOVE experimental IPIs) but flagged as over-annotation.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: a systematic map of ?14,000 high-quality human binary protein-protein
        interactions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: Binary protein-protein interaction (with CREB3L1, UniProtKB:Q96BA8) recorded
      by an alternative-splicing interactome screen. Uninformative protein-binding term
      that does not describe PGAP2's GPI-remodeling molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome map is uninformative;
      retained per policy but flagged as over-annotation.
    supported_by:
    - reference_id: PMID:26871637
      supporting_text: Alternatively-spliced isoforms of proteins exhibit strikingly
        different
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  isoform: Q9UHJ9-5
  review:
    summary: Multiple binary protein-protein interactions recorded for isoform 5 by the
      HuRI reference interactome (yeast two-hybrid). These are uninformative protein-binding
      annotations that do not describe PGAP2's molecular function; the isoform field
      records that isoform 5 was the tested clone, not an isoform-specific function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a systematic Y2H interactome map (HuRI) is
      uninformative for PGAP2's function; retained per policy but flagged as over-annotation.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions,
        or 'HuRI'
- term:
    id: GO:0120574
    label: GPI anchor remodelling
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: GPI anchor remodelling captures PGAP2's specific role most accurately - the
      post-attachment Golgi fatty-acid remodeling in which the lyso-GPI intermediate is
      reacylated with a saturated stearoyl chain. Transferred by sequence similarity from
      the mouse ortholog (UniProtKB:Q2ABP3).
    action: ACCEPT
    reason: Most specific and accurate BP for PGAP2; consistent with UniProt function and
      the PMID:29374258 mechanistic description of PGAP2 reacylation.
    supported_by:
    - reference_id: file:human/PGAP2/PGAP2-uniprot.txt
      supporting_text: second step of the fatty acid remodeling, by reacylating a lyso-GPI
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:10585768
  qualifier: located_in
  review:
    summary: Experimentally supported Golgi membrane localization for PGAP2/FRAG1, the
      core site where PGAP2 performs GPI fatty-acid remodeling. The original report
      characterized FRAG1 as an integral membrane protein with multiple membrane-spanning
      segments; the Golgi assignment reflects the full-text/curated localization.
    action: ACCEPT
    reason: Core cellular component; experimental annotation consistent with UniProt
      subcellular location (Golgi apparatus membrane, multi-pass).
    supported_by:
    - reference_id: PMID:10585768
      supporting_text: hydropathy analysis predicted FRAG1 to encode an integral membrane
    - reference_id: file:human/PGAP2/PGAP2-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:23561846
  qualifier: involved_in
  review:
    summary: Direct experimental evidence that PGAP2 is required for GPI-anchor maturation
      and surface expression of GPI-anchored proteins. Rescue of PGAP2-deficient CHO cells
      with wild-type versus HPMRS3-mutant PGAP2 showed reduced cell-surface DAF and CD59
      with the mutants, demonstrating PGAP2's role in the GPI-anchor process.
    action: ACCEPT
    reason: Core biological process supported by direct functional (rescue) experiments;
      also the basis for the HPMRS3 disease association.
    supported_by:
    - reference_id: PMID:23561846
      supporting_text: less expression of cell-surface GPI-anchored proteins DAF and CD59
        than
    - reference_id: PMID:23561846
      supporting_text: PGAP2 encodes a protein involved in remodeling the
        glycosylphosphatidylinositol
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:29374258
  qualifier: involved_in
  review:
    summary: Although this paper primarily characterizes PGAP4, its full text places PGAP2
      in the Golgi GPI fatty-acid remodeling pathway and uses PGAP2 in the GPI-remodeling
      context; the experimental (IMP) annotation to the GPI-anchor biosynthetic process
      is consistent with PGAP2's established role. Retained as core.
    action: ACCEPT
    reason: Experimental annotation for the core biological process; full text (available)
      explicitly assigns PGAP2 the reacylation step of Golgi fatty-acid remodeling. Defer
      to curator on the IMP evidence.
    supported_by:
    - reference_id: PMID:29374258
      supporting_text: In the Golgi, GPI-APs undergo fatty acid remodeling where PGAP3
        removes an sn-2-linked unsaturated fatty acid and PGAP2 is involved in reacylation
        with stearic acid, a
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Golgi membrane localization transferred by sequence similarity from the mouse
      ortholog (UniProtKB:Q2ABP3). Duplicates the experimentally supported Golgi membrane
      location.
    action: ACCEPT
    reason: Correct core location; concordant with the EXP and IEA Golgi annotations.
    supported_by:
    - reference_id: file:human/PGAP2/PGAP2-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ER-membrane localization transferred by sequence similarity from the mouse
      ortholog. As with the IBA ER annotation, this is plausible given the ER-to-Golgi
      span of the GPI pathway, but the core, experimentally supported location for PGAP2's
      remodeling function is the Golgi.
    action: KEEP_AS_NON_CORE
    reason: Plausible but non-core; PGAP2's fatty-acid remodeling step and its documented
      subcellular location are Golgi, not ER.
    supported_by:
    - reference_id: file:human/PGAP2/PGAP2-uniprot.txt
      supporting_text: Golgi apparatus membrane
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:10585768
  qualifier: located_in
  review:
    summary: Original characterization of FRAG1/PGAP2 as an integral membrane protein with
      multiple membrane-spanning segments. The generic membrane term is correct but
      uninformative; PGAP2 is a multi-pass Golgi-membrane protein.
    action: MODIFY
    reason: The generic membrane term is too general; the specific location is the Golgi
      membrane, which is separately and experimentally annotated.
    proposed_replacement_terms:
    - id: GO:0000139
      label: Golgi membrane
    supported_by:
    - reference_id: PMID:10585768
      supporting_text: hydropathy analysis predicted FRAG1 to encode an integral membrane
    - reference_id: file:human/PGAP2/PGAP2-uniprot.txt
      supporting_text: Multi-pass membrane
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/PGAP2/PGAP2-uniprot.txt
  title: UniProtKB entry Q9UHJ9 (PGAP2_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record; source of the fatty-acid remodeling function,
      Golgi apparatus membrane localization, multi-pass topology, and HPMRS3 disease
      association. Quotes verified as verbatim substrings.
- id: PMID:10585768
  title: Human FRAG1 encodes a novel membrane-spanning protein that localizes to chromosome
    11p15.5, a region of frequent loss of heterozygosity in cancer.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original cloning of FRAG1 (=PGAP2); establishes multi-pass membrane
      topology and ubiquitous expression. Golgi assignment is from the full text / curated
      record (abstract does not state Golgi). Basis for the EXP Golgi and TAS membrane
      annotations.
- id: PMID:23561846
  title: Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein,
    cause autosomal-recessive intellectual disability.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct functional evidence - CHO rescue with WT vs mutant PGAP2 alters
      surface DAF/CD59; establishes HPMRS3. Basis for the IDA GPI-anchor annotation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput binary interactome map; source of a single uninformative
      protein-binding IPI. Does not inform PGAP2's molecular function.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Alternative-splicing interactome screen; source of an uninformative
      protein-binding IPI. Does not inform PGAP2's molecular function.
- id: PMID:29374258
  title: Identification of a Golgi GPI-N-acetylgalactosamine transferase with tandem
    transmembrane regions in the catalytic domain.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primarily a PGAP4 paper, but the full text gives the clearest verbatim
      description of PGAP2's role (Golgi reacylation with stearic acid after PGAP3);
      cited for the IMP GPI-anchor annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI reference Y2H interactome; source of multiple uninformative
      protein-binding IPIs on isoform 5. Does not inform PGAP2's molecular function.
core_functions:
- description: PGAP2 acts in the Golgi to carry out (or to be required for) the second
    step of GPI fatty-acid remodeling, reacylating the lyso-GPI intermediate with a
    saturated stearoyl chain after PGAP3 removes the sn-2 unsaturated fatty acid; this
    generates the mature, lipid-raft-associating GPI anchor needed for stable cell-surface
    expression of GPI-anchored proteins.
  directly_involved_in:
  - id: GO:0120574
    label: GPI anchor remodelling
  locations:
  - id: GO:0000139
    label: Golgi membrane
  supported_by:
  - reference_id: file:human/PGAP2/PGAP2-uniprot.txt
    supporting_text: second step of the fatty acid remodeling, by reacylating a lyso-GPI
  - reference_id: PMID:29374258
    supporting_text: In the Golgi, GPI-APs undergo fatty acid remodeling where PGAP3
      removes an sn-2-linked unsaturated fatty acid and PGAP2 is involved in reacylation
      with stearic acid, a
- description: PGAP2 is required for GPI-anchor biosynthesis/maturation; loss of function
    reduces cell-surface expression of GPI-anchored proteins (e.g. DAF/CD55, CD59), and
    hypomorphic variants cause HPMRS3.
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0000139
    label: Golgi membrane
  supported_by:
  - reference_id: PMID:23561846
    supporting_text: less expression of cell-surface GPI-anchored proteins DAF and CD59
      than
suggested_questions:
- question: Is PGAP2 itself the sn-2 acyltransferase (EC 2.3.-.-) that reacylates lyso-GPI
    with stearoyl-CoA, or an accessory factor required for the reaction? The catalytic
    activity and EC number are currently assigned only by similarity.
- question: Which residues constitute the catalytic/substrate-binding site, and do the
    HPMRS3 hypomorphic variants (e.g. Y99C, R177P, T160I) impair catalysis, substrate
    binding, or protein stability?
suggested_experiments:
- description: Reconstitute the reacylation reaction in vitro with purified PGAP2, lyso-GPI
    substrate, and stearoyl-CoA to test whether PGAP2 has intrinsic acyltransferase
    activity.
- description: Mass-spectrometry lipidomics of GPI anchors from PGAP2-knockout versus
    rescued cells to confirm accumulation of lyso-GPI and loss of the stearoyl-remodeled
    species.