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).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0180046 GPI anchored protein biosynthesis | IBA GO_REF:0000033 | ACCEPT | 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). 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. 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 saturated fatty acid |
| GO:0000139 Golgi membrane | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/PGAP3/PGAP3-uniprot.txt SUBCELLULAR LOCATION: Golgi apparatus membrane 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 saturated fatty acid |
| GO:0016788 hydrolase activity, acting on ester bonds | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/PGAP3/PGAP3-uniprot.txt May catalyze the first step of the fatty acid PMID:17021251 PER1 is required for the production of lyso-GPI, suggesting that Per1p possesses or regulates the GPI-phospholipase A2 activity |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic (UniProt SubCell mapping SL-0134) annotation to Golgi membrane. Consistent with the experimentally supported Golgi localization. Reason: Redundant with the IDA and IBA Golgi membrane annotations and correctly derived from the curated UniProt subcellular location. Supporting Evidence: file:human/PGAP3/PGAP3-uniprot.txt SUBCELLULAR LOCATION: Golgi apparatus membrane |
| GO:0006506 GPI anchor biosynthetic process | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:24439110 identified mutations in PGAP3, encoding a protein that is involved in GPI-anchor maturation |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:32814053 candidate interactions and is generated by systematic yeast two-hybrid |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:33961781 The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 interactions |
| GO:0120574 GPI anchor remodelling | IMP PMID:17021251 PER1 is required for GPI-phospholipase A2 activity and invol... | ACCEPT | 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. 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. Supporting Evidence: PMID:17021251 We also found that human PERLD1 is a functional homologue of PER1 PMID:17021251 PER1 is required for the production of lyso-GPI, suggesting that Per1p possesses or regulates the GPI-phospholipase A2 activity |
| GO:0120574 GPI anchor remodelling | IMP PMID:24439110 Mutations in PGAP3 impair GPI-anchor maturation, causing a s... | ACCEPT | 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. 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. Supporting Evidence: PMID:24439110 the later GPI-anchor remodelling steps for normal neuronal development PMID:24439110 functional studies on Chinese hamster ovary cell lines |
| GO:0180046 GPI anchored protein biosynthesis | IMP PMID:29374258 Identification of a Golgi GPI-N-acetylgalactosamine transfer... | ACCEPT | 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. 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. 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 saturated fatty acid |
| GO:0000139 Golgi membrane | IDA PMID:24439110 Mutations in PGAP3 impair GPI-anchor maturation, causing a s... | ACCEPT | 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). Reason: Direct experimental evidence for the steady-state Golgi membrane localization where PGAP3 acts; the primary and most reliable localization annotation. Supporting Evidence: file:human/PGAP3/PGAP3-uniprot.txt SUBCELLULAR LOCATION: Golgi apparatus membrane |
| GO:0031410 cytoplasmic vesicle | IDA PMID:12460457 Identification of the CAB2/hCOS16 gene required for the repa... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:12460457 CAB2 translocates into vesicles |
| GO:0006506 GPI anchor biosynthetic process | IMP PMID:29374258 Identification of a Golgi GPI-N-acetylgalactosamine transfer... | ACCEPT | 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. 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. 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 saturated fatty acid |
| GO:0016788 hydrolase activity, acting on ester bonds | IMP PMID:17021251 PER1 is required for GPI-phospholipase A2 activity and invol... | ACCEPT | 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. 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. Supporting Evidence: PMID:17021251 PER1 is required for the production of lyso-GPI, suggesting that Per1p possesses or regulates the GPI-phospholipase A2 activity |
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