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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006506 GPI anchor biosynthetic process | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:29374258 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 |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/PGAP2/PGAP2-uniprot.txt Golgi apparatus membrane |
| GO:0000139 Golgi membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Golgi membrane localization derived from InterPro/UniProt automated pipelines. This is the core, experimentally supported location where PGAP2 performs GPI fatty-acid remodeling. Reason: Correct core cellular component; concordant with the EXP annotation (PMID:10585768) and UniProt subcellular location. Supporting Evidence: file:human/PGAP2/PGAP2-uniprot.txt Golgi apparatus membrane |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:25416956 a systematic map of ?14,000 high-quality human binary protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | MARK AS OVER ANNOTATED | 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. Reason: Bare protein binding from a high-throughput interactome map is uninformative; retained per policy but flagged as over-annotation. Supporting Evidence: PMID:26871637 Alternatively-spliced isoforms of proteins exhibit strikingly different |
| GO:0005515 protein binding | IPI Q9UHJ9-5 PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0120574 GPI anchor remodelling | ISS GO_REF:0000024 | ACCEPT | 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). Reason: Most specific and accurate BP for PGAP2; consistent with UniProt function and the PMID:29374258 mechanistic description of PGAP2 reacylation. Supporting Evidence: file:human/PGAP2/PGAP2-uniprot.txt second step of the fatty acid remodeling, by reacylating a lyso-GPI |
| GO:0000139 Golgi membrane | EXP PMID:10585768 Human FRAG1 encodes a novel membrane-spanning protein that l... | ACCEPT | 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. Reason: Core cellular component; experimental annotation consistent with UniProt subcellular location (Golgi apparatus membrane, multi-pass). Supporting Evidence: PMID:10585768 hydropathy analysis predicted FRAG1 to encode an integral membrane file:human/PGAP2/PGAP2-uniprot.txt Golgi apparatus membrane |
| GO:0006506 GPI anchor biosynthetic process | IDA PMID:23561846 Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remode... | ACCEPT | 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. Reason: Core biological process supported by direct functional (rescue) experiments; also the basis for the HPMRS3 disease association. Supporting Evidence: PMID:23561846 less expression of cell-surface GPI-anchored proteins DAF and CD59 than PMID:23561846 PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol |
| GO:0006506 GPI anchor biosynthetic process | IMP PMID:29374258 Identification of a Golgi GPI-N-acetylgalactosamine transfer... | ACCEPT | 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. 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. Supporting Evidence: PMID:29374258 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 |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Golgi membrane localization transferred by sequence similarity from the mouse ortholog (UniProtKB:Q2ABP3). Duplicates the experimentally supported Golgi membrane location. Reason: Correct core location; concordant with the EXP and IEA Golgi annotations. Supporting Evidence: file:human/PGAP2/PGAP2-uniprot.txt Golgi apparatus membrane |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. Reason: Plausible but non-core; PGAP2's fatty-acid remodeling step and its documented subcellular location are Golgi, not ER. Supporting Evidence: file:human/PGAP2/PGAP2-uniprot.txt Golgi apparatus membrane |
| GO:0016020 membrane | TAS PMID:10585768 Human FRAG1 encodes a novel membrane-spanning protein that l... | MODIFY | 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. Reason: The generic membrane term is too general; the specific location is the Golgi membrane, which is separately and experimentally annotated. Proposed replacements: Golgi membrane Supporting Evidence: PMID:10585768 hydropathy analysis predicted FRAG1 to encode an integral membrane file:human/PGAP2/PGAP2-uniprot.txt Multi-pass membrane |
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Download this section (compressed HTML)Q: 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.
Q: 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?
Experiment: Reconstitute the reacylation reaction in vitro with purified PGAP2, lyso-GPI substrate, and stearoyl-CoA to test whether PGAP2 has intrinsic acyltransferase activity.
Experiment: 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.
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