id: Q96FM1
gene_symbol: PGAP3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PGAP3 (Post-GPI Attachment to Proteins factor 3; PERLD1; CAB2/hCOS16)
  is a Golgi multi-pass membrane protein that acts as a GPI-specific phospholipase
  A2 in the fatty-acid remodeling of glycosylphosphatidylinositol (GPI) anchors. It
  catalyzes the first remodeling step, removing the unsaturated (sn-2) fatty acyl
  chain from the inositol phospholipid of the mature GPI anchor to generate a lyso-GPI
  intermediate; PGAP2 then reacylates the anchor with a saturated (stearoyl) chain.
  This remodeling is required for GPI-anchored proteins to associate with membrane
  microdomains (lipid rafts) at the cell surface. PGAP3 is the functional ortholog
  of yeast Per1p. Loss of function causes hyperphosphatasia with impaired intellectual
  development syndrome 4 (HPMRS4 / Mabry syndrome), an autosomal recessive disorder
  with developmental delay, intellectual disability and elevated serum alkaline phosphatase
  (a GPI-anchored enzyme).
alternative_products:
- name: '1'
  id: Q96FM1-1
- name: '2'
  id: Q96FM1-2
  sequence_note: VSP_034158
- name: '3'
  id: Q96FM1-3
  sequence_note: VSP_057229
existing_annotations:
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation to the overall pathway of GPI-anchored protein
      biosynthesis. PGAP3 performs a Golgi lipid-remodeling step required for GPI-APs
      to reach a fully functional, raft-associated state, so involvement in this broad
      process is well supported. A more specific remodeling term is also annotated
      (GO:0120574).
    action: ACCEPT
    reason: Consistent with the established role of PGAP3 in GPI-anchor maturation;
      IBA is at an appropriate pathway-level of specificity for this multi-step process.
    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 saturated fatty acid
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) is_active_in Golgi membrane. This matches the experimentally
      determined steady-state localization of PGAP3 and the compartment where fatty-acid
      remodeling of GPI anchors occurs.
    action: ACCEPT
    reason: The Golgi membrane is where PGAP3 carries out its remodeling activity;
      supported by IDA localization and by the known Golgi site of GPI fatty-acid remodeling.
    supported_by:
    - reference_id: file:human/PGAP3/PGAP3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Golgi apparatus membrane'
    - 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 saturated fatty acid
- term:
    id: GO:0016788
    label: hydrolase activity, acting on ester bonds
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) molecular-function annotation as an ester-bond hydrolase.
      PGAP3 is a GPI-specific phospholipase A2 (EC 3.1.1.-) that hydrolyzes the ester
      bond linking the sn-2 unsaturated fatty acid to the GPI inositol phospholipid,
      so ester-bond hydrolase activity is correct, if general.
    action: ACCEPT
    reason: Correct at the family/phylogenetic level; the phospholipase A2 (acyl-ester
      hydrolase) activity of PGAP3 is a specialization of this ester-bond hydrolase
      term. A more specific phospholipase A2 term would be an appropriate refinement.
    supported_by:
    - reference_id: file:human/PGAP3/PGAP3-uniprot.txt
      supporting_text: May catalyze the first step of the fatty acid
    - reference_id: PMID:17021251
      supporting_text: "PER1 is required for the production of \nlyso-GPI, suggesting\
        \ that Per1p possesses or regulates the GPI-phospholipase A2 \nactivity"
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic (UniProt SubCell mapping SL-0134) annotation to Golgi membrane.
      Consistent with the experimentally supported Golgi localization.
    action: ACCEPT
    reason: Redundant with the IDA and IBA Golgi membrane annotations and correctly
      derived from the curated UniProt subcellular location.
    supported_by:
    - reference_id: file:human/PGAP3/PGAP3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Golgi apparatus membrane'
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Electronic (InterPro IPR007217, Per1-like) annotation to GPI anchor biosynthetic
      process. The Per1-like family carries out GPI-anchor lipid remodeling, part of
      the overall biosynthetic/maturation pathway.
    action: ACCEPT
    reason: The InterPro-to-GO mapping is biologically appropriate for the PGAP3/Per1
      family; PGAP3 acts in GPI-anchor maturation. Duplicated by experimental IMP annotations
      to the same term.
    supported_by:
    - reference_id: PMID:24439110
      supporting_text: "identified mutations in PGAP3, encoding a protein that is involved\
        \ in GPI-anchor \nmaturation"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: IPI 'protein binding' from a large-scale neurodegenerative-disease interactome
      (yeast two-hybrid) reporting an interaction with GTF3C3 (Q9Y5Q9). This is an
      uninformative bare protein-binding term from a high-throughput screen with no
      established functional relationship to GPI remodeling.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'GO:0005515 protein binding conveys no specific molecular function; the
      interactor (GTF3C3, a TFIIIC transcription-factor subunit) has no known connection
      to GPI-anchor biology, and the evidence is a single high-throughput Y2H hit.
      Retained (not removed) per policy on experimental IPI annotations.'
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: candidate interactions and is generated by systematic yeast
        two-hybrid
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IPI 'protein binding' from the BioPlex proteome-scale AP-MS interactome
      reporting an interaction with TBRG4 (Q969Z0). Bare protein-binding term from
      a high-throughput screen without an established functional link to PGAP3's remodeling
      role.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'GO:0005515 protein binding is uninformative; the interactor (TBRG4, a
      mitochondrial RNA-processing protein) has no known relationship to Golgi GPI
      remodeling, and the evidence is a single proteome-scale AP-MS association. Retained
      (not removed) per policy on experimental IPI annotations.'
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: "The first, BioPlex 3.0, results from affinity purification \n\
        of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162\
        \ \ninteractions"
- term:
    id: GO:0120574
    label: GPI anchor remodelling
  evidence_type: IMP
  original_reference_id: PMID:17021251
  qualifier: involved_in
  review:
    summary: IMP to GPI anchor remodelling based on the yeast PER1 study, which established
      PER1 as required for GPI lipid remodeling (production of lyso-GPI / GPI-phospholipase
      A2 activity) and showed that human PERLD1 (PGAP3) is a functional homolog of
      PER1. This is the most specific and accurate BP term for PGAP3.
    action: ACCEPT
    reason: Directly captures the core evolved function of PGAP3 - remodeling of the
      GPI anchor after its attachment to protein - and is supported by cross-species
      complementation demonstrating conserved function.
    supported_by:
    - reference_id: PMID:17021251
      supporting_text: We also found that human PERLD1 is a functional homologue of
        PER1
    - reference_id: PMID:17021251
      supporting_text: "PER1 is required for the production of \nlyso-GPI, suggesting\
        \ that Per1p possesses or regulates the GPI-phospholipase A2 \nactivity"
- term:
    id: GO:0120574
    label: GPI anchor remodelling
  evidence_type: IMP
  original_reference_id: PMID:24439110
  qualifier: involved_in
  review:
    summary: IMP to GPI anchor remodelling from the human genetics/functional study
      showing that biallelic PGAP3 loss-of-function variants impair GPI-anchor maturation,
      cause elevated surface expression of abnormally remodeled GPI-APs, and are validated
      in CHO functional assays. This is the core, most specific BP for PGAP3.
    action: ACCEPT
    reason: Well-supported experimental annotation to the specific remodeling process;
      patient variants and CHO cell functional studies demonstrate PGAP3's role in
      the later GPI-anchor remodeling steps.
    supported_by:
    - reference_id: PMID:24439110
      supporting_text: "the later \nGPI-anchor remodelling steps for normal neuronal\
        \ development"
    - reference_id: PMID:24439110
      supporting_text: functional studies on Chinese hamster ovary cell lines
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IMP
  original_reference_id: PMID:29374258
  qualifier: involved_in
  review:
    summary: IMP to GPI anchored protein biosynthesis from the PGAP4 study, in which
      PGAP3-knockout cells were used and the Golgi fatty-acid remodeling role of PGAP3
      (removal of the sn-2 unsaturated fatty acid, before PGAP2 reacylation) is directly
      described. Supports involvement in the broad GPI-AP biosynthesis/maturation pathway.
    action: ACCEPT
    reason: PGAP3 performs an obligatory Golgi remodeling step in producing mature,
      functional GPI-anchored proteins; the annotation is at an appropriate pathway
      level and is duplicated by the IBA annotation to the same term.
    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 saturated fatty acid
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IDA
  original_reference_id: PMID:24439110
  qualifier: located_in
  review:
    summary: IDA localization to the Golgi membrane. The HPMRS4 study characterized
      wild-type and mutant PGAP3 localization, confirming Golgi apparatus residence
      of the wild-type protein (with ER retention of certain pathogenic mutants).
    action: ACCEPT
    reason: Direct experimental evidence for the steady-state Golgi membrane localization
      where PGAP3 acts; the primary and most reliable localization annotation.
    supported_by:
    - reference_id: file:human/PGAP3/PGAP3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Golgi apparatus membrane'
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IDA
  original_reference_id: PMID:12460457
  qualifier: located_in
  review:
    summary: IDA to cytoplasmic vesicle from the early CAB2/hCOS16 study, which reported
      that a CAB2 (PGAP3)-GFP fusion translocated into vesicles. This predates recognition
      of PGAP3 as a GPI-remodeling enzyme; the well-established, functionally relevant
      location is the Golgi.
    action: KEEP_AS_NON_CORE
    reason: Localization to vesicular structures is plausible for a secretory-pathway
      membrane protein but is peripheral to PGAP3's core Golgi remodeling function
      and derives from an overexpressed GFP-fusion in a study focused on chromosome
      17q12 amplicon genes, not GPI biology.
    supported_by:
    - reference_id: PMID:12460457
      supporting_text: CAB2 translocates into vesicles
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:29374258
  qualifier: involved_in
  review:
    summary: IMP to GPI anchor biosynthetic process (UniProt-assigned), supported by
      the same functional context in which PGAP3 performs the Golgi fatty-acid remodeling
      step of GPI-anchor maturation. Duplicates the InterPro IEA annotation to the
      same term.
    action: ACCEPT
    reason: Correct pathway-level BP for PGAP3's role in producing mature GPI anchors;
      the remodeling activity is an integral part of GPI-anchor biosynthesis/maturation.
    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 saturated fatty acid
- term:
    id: GO:0016788
    label: hydrolase activity, acting on ester bonds
  evidence_type: IMP
  original_reference_id: PMID:17021251
  qualifier: enables
  review:
    summary: IMP molecular-function annotation as an ester-bond hydrolase, based on
      the PER1 study demonstrating that PER1/PERLD1(PGAP3) is required for GPI-phospholipase
      A2 activity and lyso-GPI production. PGAP3 hydrolyzes the sn-2 acyl-ester bond
      of the GPI inositol phospholipid.
    action: ACCEPT
    reason: The phospholipase A2 (acyl-ester hydrolase) activity of PGAP3 is a specific
      instance of ester-bond hydrolase activity; a dedicated phospholipase A2 term
      would be an appropriate future refinement.
    supported_by:
    - reference_id: PMID:17021251
      supporting_text: "PER1 is required for the production of \nlyso-GPI, suggesting\
        \ that Per1p possesses or regulates the GPI-phospholipase A2 \nactivity"
core_functions:
- description: GPI-specific phospholipase A2 that hydrolyzes the ester bond linking
    the unsaturated (sn-2) fatty acyl chain to the inositol phospholipid of the mature
    GPI anchor, generating a lyso-GPI intermediate - the first step of Golgi GPI fatty-acid
    remodeling (before PGAP2 reacylation with a saturated stearoyl chain).
  molecular_function:
    id: GO:0016788
    label: hydrolase activity, acting on ester bonds
  directly_involved_in:
  - id: GO:0120574
    label: GPI anchor remodelling
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0000139
    label: Golgi membrane
  supported_by:
  - reference_id: file:human/PGAP3/PGAP3-uniprot.txt
    supporting_text: Involved in the fatty acid remodeling steps of GPI-anchor
  - reference_id: file:human/PGAP3/PGAP3-uniprot.txt
    supporting_text: removing the unsaturated acyl chain at sn-2 of inositol
  - reference_id: file:human/PGAP3/PGAP3-uniprot.txt
    supporting_text: generating a lyso-GPI intermediate
  - reference_id: PMID:17021251
    supporting_text: "PER1 is required for the production of \nlyso-GPI, suggesting\
      \ that Per1p possesses or regulates the GPI-phospholipase A2 \nactivity"
  - 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 saturated fatty acid
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: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: file:human/PGAP3/PGAP3-uniprot.txt
  title: UniProtKB entry Q96FM1 (PGAP3_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record; source for FUNCTION, CATALYTIC ACTIVITY (Rhea
      RHEA:83847, EC 3.1.1.-), Golgi subcellular location, topology, and HPMRS4 disease
      association.
- id: PMID:12460457
  title: Identification of the CAB2/hCOS16 gene required for the repair of DNA double-strand
    breaks on a core amplified region of the 17q12 locus in breast and gastric cancers.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: First cloning of CAB2/hCOS16 (=PGAP3) as a 17q12 amplicon gene; reports
      GFP-fusion translocation into vesicles. Predates the enzymatic characterization;
      DNA-repair/Mn2+ framing is not related to PGAP3's GPI-remodeling function.
- id: PMID:17021251
  title: PER1 is required for GPI-phospholipase A2 activity and involved in lipid
    remodeling of GPI-anchored proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the GPI-phospholipase A2 / lyso-GPI-forming activity of
      the PER1 family and shows human PERLD1 (PGAP3) functionally complements yeast
      per1; foundational for PGAP3's molecular function.
- id: PMID:24439110
  title: Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia
    with mental retardation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Human genetics plus CHO functional studies defining HPMRS4 and confirming
      PGAP3's role in GPI-anchor remodeling; source of Golgi IDA localization and disease
      variants.
- id: PMID:29374258
  title: Identification of a Golgi GPI-N-acetylgalactosamine transferase with tandem
    transmembrane regions in the catalytic domain.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PGAP4 paper; used PGAP3-knockout cells and gives a clear verbatim
      description of PGAP3 removing the sn-2 unsaturated fatty acid in Golgi GPI remodeling
      (before PGAP2 reacylation).
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale Y2H neurodegenerative-disease interactome; source of the
      GTF3C3 protein-binding IPI. High-throughput; no established functional link to
      PGAP3's GPI-remodeling role.
- 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 proteome-scale AP-MS interactome; source of the TBRG4 protein-binding
      IPI. High-throughput; no established functional link to PGAP3.