id: Q75T13
gene_symbol: PGAP1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PGAP1 (GPI inositol-deacylase; Post-GPI Attachment to Proteins factor
  1) is a multi-pass endoplasmic reticulum membrane protein with an alpha/beta-hydrolase
  (serine-hydrolase) fold. After a nascent protein has received its glycosylphosphatidylinositol
  (GPI) anchor from the GPI transamidase, PGAP1 removes the acyl chain that is linked
  to the 2-OH of the inositol ring of the anchor. This inositol-deacylation is the
  first, ER-resident step of the post-attachment GPI-anchor remodeling pathway and
  is required for efficient export of GPI-anchored proteins from the ER to the Golgi
  (via recognition of the remodeled anchor by p24-family cargo receptors that load
  GPI-anchored proteins into COPII vesicles). Biallelic loss-of-function variants
  cause an autosomal-recessive inherited GPI-deficiency disorder (GPI biosynthesis
  defect; NEDDSBA, MIM:615802) with global developmental delay, impaired intellectual
  development, hypotonia/spasticity, epilepsy and structural brain abnormalities;
  in this disorder cell-surface levels of GPI-anchored proteins are near-normal but
  the anchor fine structure is abnormal (PI-PLC-resistant), reflecting a remodeling
  rather than an attachment defect.
alternative_products:
- name: '1'
  id: Q75T13-1
- name: '2'
  id: Q75T13-2
  sequence_note: VSP_023040
- name: '3'
  id: Q75T13-3
  sequence_note: VSP_023042, VSP_023043
- name: '4'
  id: Q75T13-4
  sequence_note: VSP_023041, VSP_023044
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation placing PGAP1 activity in the endoplasmic
      reticulum. This is correct - PGAP1 is an ER-resident enzyme that acts on the
      GPI anchor immediately after attachment in the ER.
    action: ACCEPT
    reason: Consistent with experimental localization and function; PGAP1 acts on
      nascent GPI-anchored proteins in the ER. The more precise term ER membrane (GO:0005789)
      is also annotated and is captured in core_functions.
    supported_by:
    - reference_id: PMID:24784135
      supporting_text: PGAP1 is a deacylase that removes an acyl-chain from the inositol
        of GPI anchors in the endoplasmic reticulum immediately after attachment of
        GPI to proteins.
    - reference_id: PMID:38167496
      supporting_text: Residing in the ER membrane, PGAP1 removes the inositol-linked
        acyl chain from nascent triacylated GPI-APs (dubbed GPI-AP3) to form the diacylated
        forms.
- term:
    id: GO:0160215
    label: deacylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) annotation of deacylase activity - the core molecular
      function of PGAP1 as a GPI inositol-deacylase. GO:0160215 (current label "deacylase
      activity") is the most specific currently available GO molecular-function term
      for this activity; there is no dedicated "GPI inositol-deacylase activity" term.
    action: ACCEPT
    reason: This is the defining, experimentally supported molecular function of PGAP1
      (removal of the inositol-linked acyl chain of the GPI anchor). Retained as a
      core function.
    supported_by:
    - reference_id: PMID:38167496
      supporting_text: Residing in the ER membrane, PGAP1 removes the inositol-linked
        acyl chain from nascent triacylated GPI-APs (dubbed GPI-AP3) to form the diacylated
        forms.
    - reference_id: PMID:24784135
      supporting_text: PGAP1 is a deacylase that removes an acyl-chain from the inositol
        of GPI anchors in the endoplasmic reticulum immediately after attachment of
        GPI to proteins.
- 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
      mapping placing PGAP1 in the ER membrane. PGAP1 is a multi-pass ER membrane
      protein, so this is correct and is the most precise localization term.
    action: ACCEPT
    reason: Correct localization; PGAP1 is a multi-pass ER membrane protein acting
      on the luminal face of the anchor. Retained in core_functions.
    supported_by:
    - reference_id: file:human/PGAP1/PGAP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
    - reference_id: PMID:38167496
      supporting_text: Residing in the ER membrane, PGAP1 removes the inositol-linked
        acyl chain from nascent triacylated GPI-APs (dubbed GPI-AP3) to form the diacylated
        forms.
- term:
    id: GO:0016788
    label: hydrolase activity, acting on ester bonds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-to-GO electronic annotation assigning ester-bond hydrolase activity
      based on the alpha/beta-hydrolase (PGAP1/BST1) domains. This is a correct but
      broad parent of the specific deacylase activity; PGAP1 hydrolyzes an ester bond
      to release the inositol-linked fatty acid.
    action: ACCEPT
    reason: Biologically accurate broader classification (carboxylic-ester hydrolase;
      EC 3.1.-.-). It is a general parent of the more specific deacylase activity
      (GO:0160215) but is not wrong, so it is retained. The specific deacylase term
      is captured as the core molecular function.
    supported_by:
    - reference_id: PMID:38167496
      supporting_text: serine hydrolase-type catalysis
    - reference_id: file:human/PGAP1/PGAP1-uniprot.txt
      supporting_text: 'SIMILARITY: Belongs to the GPI inositol-deacylase family.'
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162791
  qualifier: involved_in
  review:
    summary: Reactome traceable annotation placing PGAP1 in the "Attachment of GPI
      anchor to uPAR" pathway. PGAP1 does not catalyze the transamidase attachment
      step; it acts immediately after attachment, deacylating the inositol of the
      already-transferred anchor as the first post-attachment remodeling step.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term overstates PGAP1's role. The transamidase (PIGK/GPAA1/PIGS/PIGT/PIGU)
      attaches the GPI anchor to the protein; PGAP1 acts downstream on the anchor
      that has already been attached. Reactome groups the deacylation reaction within
      the broader attachment pathway (so the annotation is not entirely wrong at the
      pathway level), but a GPI anchor biosynthetic/remodeling process term better
      reflects the direct role. The correct core BP (GPI anchor biosynthetic process,
      GO:0006506; the post-attachment remodeling step) is captured in core_functions.
    supported_by:
    - reference_id: PMID:24784135
      supporting_text: PGAP1 is a deacylase that removes an acyl-chain from the inositol
        of GPI anchors in the endoplasmic reticulum immediately after attachment of
        GPI to proteins.
    - reference_id: Reactome:R-HSA-162791
      supporting_text: In a second step, the GPI moiety is deacylated, yielding a uPAR-GPI
        conjugate that can be efficiently transported to the Golgi apparatus.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS annotation transferring ER membrane localization from the mouse ortholog
      (UniProtKB:Q765A7). Consistent with the multi-pass ER membrane topology of PGAP1.
    action: ACCEPT
    reason: Correct localization, consistent with the SubCell-based IEA, the Reactome
      TAS, and the multi-pass membrane topology annotated in UniProt.
    supported_by:
    - reference_id: file:human/PGAP1/PGAP1-uniprot.txt
      supporting_text: Multi-pass membrane protein
    - reference_id: PMID:38167496
      supporting_text: Residing in the ER membrane, PGAP1 removes the inositol-linked
        acyl chain from nascent triacylated GPI-APs (dubbed GPI-AP3) to form the diacylated
        forms.
- term:
    id: GO:0160215
    label: deacylase activity
  evidence_type: IDA
  original_reference_id: PMID:24784135
  qualifier: enables
  review:
    summary: Direct-assay (IDA) annotation of deacylase activity. In this study, the
      patient p.Leu197del null mutation abolished PGAP1 activity, rendering GPI-anchored
      proteins resistant to PI-PLC, and wild-type PGAP1 cDNA rescued PI-PLC sensitivity
      in PGAP1-deficient CHO cells - functionally demonstrating the inositol-deacylase
      activity.
    action: ACCEPT
    reason: Experimentally supported core molecular function (GPI inositol-deacylase);
      GO:0160215 is the most specific available term for this activity.
    supported_by:
    - reference_id: PMID:24784135
      supporting_text: PGAP1 is a deacylase that removes an acyl-chain from the inositol
        of GPI anchors in the endoplasmic reticulum immediately after attachment of
        GPI to proteins.
- term:
    id: GO:0160215
    label: deacylase activity
  evidence_type: IDA
  original_reference_id: PMID:38167496
  qualifier: enables
  review:
    summary: Direct-assay (IDA) annotation of deacylase activity from the structural/biochemical
      study, which developed a fluorescent GPI-AP substrate assay, kinetically characterized
      the enzyme, and showed a serine-hydrolase-type catalysis that removes the inositol-linked
      acyl chain from GPI-anchored proteins.
    action: ACCEPT
    reason: Experimentally supported core molecular function; the same activity as
      the other IDA annotation. Retained as core.
    supported_by:
    - reference_id: PMID:38167496
      supporting_text: Residing in the ER membrane, PGAP1 removes the inositol-linked
        acyl chain from nascent triacylated GPI-APs (dubbed GPI-AP3) to form the diacylated
        forms.
    - reference_id: PMID:38167496
      supporting_text: serine hydrolase-type catalysis
- term:
    id: GO:1902953
    label: positive regulation of ER to Golgi vesicle-mediated transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS annotation (from mouse ortholog) capturing PGAP1's role in promoting
      ER-to-Golgi transport of GPI-anchored proteins. Inositol-deacylation by PGAP1
      is required for efficient ER export of GPI-APs, mediated by binding of the remodeled
      anchor to p24-family cargo receptors that recruit GPI-APs into COPII vesicles.
    action: KEEP_AS_NON_CORE
    reason: Well-supported downstream biological consequence of PGAP1 deacylation,
      but it is a regulatory/trafficking process rather than the direct molecular
      role of the enzyme. Retained as non-core; the direct role (inositol-deacylation
      / GPI anchor remodeling) is the core function.
    supported_by:
    - reference_id: PMID:38167496
      supporting_text: in mammalian cells, the deacylation by hPGAP1 is necessary
        for efficient ER export
    - reference_id: PMID:38167496
      supporting_text: the deacylation is required for binding with p24-family cargo
        receptors
- term:
    id: GO:0016788
    label: hydrolase activity, acting on ester bonds
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162729
  qualifier: enables
  review:
    summary: Reactome traceable annotation of ester-bond hydrolase activity, based
      on the modeled reaction uPAR-acyl-GPI + H2O to uPAR + long-chain fatty acid
      in the ER. Correct broad classification of the deacylation (ester hydrolysis)
      reaction.
    action: ACCEPT
    reason: Accurate broader parent of the specific deacylase activity; the reaction
      is an ester hydrolysis releasing the inositol-linked fatty acid. Retained; the
      more specific deacylase term is the core molecular function.
    supported_by:
    - reference_id: Reactome:R-HSA-162729
      supporting_text: The fatty acid group added to inositol in the fourth step of
        GPI biosynthsis is removed from GPI-conjugated uPAR.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162729
  qualifier: located_in
  review:
    summary: Reactome traceable annotation placing the PGAP1 deacylation reaction
      at the ER membrane. Consistent with the SubCell IEA, ISS, and experimental data.
    action: ACCEPT
    reason: Correct localization; the deacylation reaction occurs in the ER.
    supported_by:
    - reference_id: Reactome:R-HSA-162729
      supporting_text: This hydrolysis event occurs in the endoplasmic reticulum
    - reference_id: PMID:38167496
      supporting_text: Residing in the ER membrane, PGAP1 removes the inositol-linked
        acyl chain from nascent triacylated GPI-APs (dubbed GPI-AP3) to form the diacylated
        forms.
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: GPI anchor biosynthetic process is the correct core biological process
      for PGAP1. PGAP1 performs the first, ER-resident step of the post-attachment
      GPI-anchor remodeling phase (inositol-deacylation). This term is present as an
      IBA:GO_Central annotation in the UniProt cross-reference block but was not in
      the seeded GOA TSV; it is added here as the appropriate replacement for the
      over-annotated GO:0016255 (attachment of GPI anchor to protein).
    action: NEW
    reason: Captures PGAP1's direct role in GPI-anchor biosynthesis/remodeling more
      accurately than the transamidase-centric GO:0016255. Supported by the UniProt
      IBA annotation and the experimental literature.
    supported_by:
    - reference_id: file:human/PGAP1/PGAP1-uniprot.txt
      supporting_text: 'GO:0006506; P:GPI anchor biosynthetic process; IBA:GO_Central.'
    - reference_id: PMID:24784135
      supporting_text: PGAP1 is a deacylase that removes an acyl-chain from the inositol
        of GPI anchors in the endoplasmic reticulum immediately after attachment of
        GPI to proteins.
core_functions:
- description: GPI inositol-deacylase that hydrolyzes and removes the acyl chain linked
    to the 2-OH of the inositol ring of the GPI anchor of a GPI-anchored protein in
    the ER, the first step of post-attachment GPI-anchor remodeling.
  molecular_function:
    id: GO:0160215
    label: deacylase activity
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:38167496
    supporting_text: Residing in the ER membrane, PGAP1 removes the inositol-linked
      acyl chain from nascent triacylated GPI-APs (dubbed GPI-AP3) to form the diacylated
      forms.
  - reference_id: PMID:24784135
    supporting_text: PGAP1 is a deacylase that removes an acyl-chain from the inositol
      of GPI anchors in the endoplasmic reticulum immediately after attachment of
      GPI to proteins.
- description: The inositol-deacylation performed by PGAP1 is required for efficient
    ER-to-Golgi transport of GPI-anchored proteins, enabling recognition of the remodeled
    anchor by p24-family cargo receptors that load GPI-APs into COPII vesicles.
  molecular_function:
    id: GO:0160215
    label: deacylase activity
  directly_involved_in:
  - id: GO:1902953
    label: positive regulation of ER to Golgi vesicle-mediated transport
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:38167496
    supporting_text: in mammalian cells, the deacylation by hPGAP1 is necessary for
      efficient ER export
  - reference_id: PMID:38167496
    supporting_text: the deacylation is required for binding with p24-family cargo
      receptors
proposed_new_terms:
- proposed_name: GPI inositol-deacylase activity
  proposed_definition: Catalysis of the hydrolytic removal of the acyl chain linked
    to the 2-position (2-O-acyl) of the inositol ring of a glycosylphosphatidylinositol
    (GPI) anchor of a GPI-anchored protein, releasing a fatty acid.
  justification: PGAP1 (and its yeast ortholog Bst1) has a specific, well-characterized
    inositol-deacylase activity on GPI anchors that is currently only representable
    by the generic term GO:0160215 (deacylase activity) or its broad parent GO:0016788
    (hydrolase activity, acting on ester bonds). A dedicated child term would capture
    the substrate specificity.
  proposed_parent:
    id: GO:0160215
    label: deacylase activity
suggested_questions:
- question: Beyond the inositol-deacylase activity, does human PGAP1 have direct roles
    in ER quality control / ERAD of misfolded GPI-anchored proteins that warrant separate
    GO annotation?
suggested_experiments:
- description: Direct kinetic and substrate-specificity characterization of purified
    recombinant human PGAP1 on defined GPI-anchored protein substrates, to formally
    establish the human enzyme's inositol-deacylase activity (current human IDA annotations
    rely on cell-based PI-PLC-sensitivity rescue rather than in vitro enzymology).
  hypothesis: Human PGAP1 directly and specifically hydrolyzes the inositol-linked
    acyl chain of GPI-anchored protein substrates.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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: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: PMID:24784135
  title: Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual
    disability and encephalopathy.
  findings:
  - statement: PGAP1 is the GPI inositol-deacylase that removes an acyl chain from
      the inositol of GPI anchors in the ER immediately after attachment of GPI to
      proteins; a homozygous null variant (p.Leu197del) causes autosomal-recessive
      intellectual disability and encephalopathy.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available and PubMed-verified; directly establishes PGAP1
      function, its ER localization, the post-attachment inositol-deacylation, and
      the human disease phenotype. Supporting quotes verified as verbatim substrings.
- id: PMID:38167496
  title: Molecular basis of the inositol deacylase PGAP1 involved in quality control
    of GPI-AP biogenesis.
  findings:
  - statement: PGAP1 resides in the ER membrane, initiates the post-attachment remodeling
      phase by removing the inositol-linked acyl chain of nascent GPI-anchored proteins
      via serine-hydrolase-type catalysis, and this deacylation is required for efficient
      ER-to-Golgi export via p24-family cargo receptors.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available and PubMed-verified; structural/biochemical
      study of the inositol-deacylase and its role in GPI-AP quality control and ER
      export. Supporting quotes verified as verbatim substrings.
- id: PMID:24482476
  title: Exome sequencing links corticospinal motor neuron disease to common neurodegenerative
    disorders.
  findings:
  - statement: Independent exome-sequencing evidence linking PGAP1 variants to the
      neurodevelopmental disorder (NEDDSBA); cited by UniProt for disease involvement.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cited by UniProt as a second reference implicating PGAP1 in the
      inherited disorder; corroborates disease relevance rather than molecular function.
- id: Reactome:R-HSA-162729
  title: uPAR-acyl-GPI + H2O -> uPAR + long-chain fatty acid
  findings:
  - statement: Models the PGAP1-catalyzed removal of the inositol-linked fatty acid
      from GPI-conjugated uPAR in the ER, associated with efficient ER-to-Golgi transport.
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction directly representing PGAP1 deacylase activity;
      title left exactly as fetched.
- id: Reactome:R-HSA-162791
  title: Attachment of GPI anchor to uPAR
  findings:
  - statement: Pathway in which the transferred GPI moiety is deacylated (by PGAP1),
      yielding a uPAR-GPI conjugate that can be efficiently transported to the Golgi.
    reference_section_type: OTHER
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Reactome pathway grouping the deacylation reaction under GPI attachment;
      title left exactly as fetched.
- id: file:human/PGAP1/PGAP1-uniprot.txt
  title: UniProtKB entry Q75T13 (PGAP1_HUMAN)
  findings:
  - statement: PGAP1 is a GPI inositol-deacylase, a multi-pass ER membrane protein
      belonging to the GPI inositol-deacylase family, with EC 3.1.-.- carboxylic-ester
      hydrolase activity; deficiency causes NEDDSBA (MIM:615802).
    reference_section_type: OTHER