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.
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.
Parent term: deacylase activity
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:24784135 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. PMID:38167496 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. |
| GO:0160215 deacylase activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:38167496 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. PMID:24784135 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. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | 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. Reason: Correct localization; PGAP1 is a multi-pass ER membrane protein acting on the luminal face of the anchor. Retained in core_functions. Supporting Evidence: file:human/PGAP1/PGAP1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane PMID:38167496 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. |
| GO:0016788 hydrolase activity, acting on ester bonds | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:38167496 serine hydrolase-type catalysis file:human/PGAP1/PGAP1-uniprot.txt SIMILARITY: Belongs to the GPI inositol-deacylase family. |
| GO:0016255 attachment of GPI anchor to protein | TAS Reactome:R-HSA-162791 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:24784135 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. Reactome:R-HSA-162791 In a second step, the GPI moiety is deacylated, yielding a uPAR-GPI conjugate that can be efficiently transported to the Golgi apparatus. |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation transferring ER membrane localization from the mouse ortholog (UniProtKB:Q765A7). Consistent with the multi-pass ER membrane topology of PGAP1. Reason: Correct localization, consistent with the SubCell-based IEA, the Reactome TAS, and the multi-pass membrane topology annotated in UniProt. Supporting Evidence: file:human/PGAP1/PGAP1-uniprot.txt Multi-pass membrane protein PMID:38167496 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. |
| GO:0160215 deacylase activity | IDA PMID:24784135 Null mutation in PGAP1 impairing Gpi-anchor maturation in pa... | ACCEPT | 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. Reason: Experimentally supported core molecular function (GPI inositol-deacylase); GO:0160215 is the most specific available term for this activity. Supporting Evidence: PMID:24784135 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. |
| GO:0160215 deacylase activity | IDA PMID:38167496 Molecular basis of the inositol deacylase PGAP1 involved in ... | ACCEPT | 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. Reason: Experimentally supported core molecular function; the same activity as the other IDA annotation. Retained as core. Supporting Evidence: PMID:38167496 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. PMID:38167496 serine hydrolase-type catalysis |
| GO:1902953 positive regulation of ER to Golgi vesicle-mediated transport | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:38167496 in mammalian cells, the deacylation by hPGAP1 is necessary for efficient ER export PMID:38167496 the deacylation is required for binding with p24-family cargo receptors |
| GO:0016788 hydrolase activity, acting on ester bonds | TAS Reactome:R-HSA-162729 | ACCEPT | 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. 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. Supporting Evidence: Reactome:R-HSA-162729 The fatty acid group added to inositol in the fourth step of GPI biosynthsis is removed from GPI-conjugated uPAR. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-162729 | ACCEPT | Summary: Reactome traceable annotation placing the PGAP1 deacylation reaction at the ER membrane. Consistent with the SubCell IEA, ISS, and experimental data. Reason: Correct localization; the deacylation reaction occurs in the ER. Supporting Evidence: Reactome:R-HSA-162729 This hydrolysis event occurs in the endoplasmic reticulum PMID:38167496 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. |
| GO:0006506 GPI anchor biosynthetic process | IBA GO_REF:0000033 | NEW | 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). 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. Supporting Evidence: file:human/PGAP1/PGAP1-uniprot.txt GO:0006506; P:GPI anchor biosynthetic process; IBA:GO_Central. PMID:24784135 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. |
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Download this section (compressed HTML)Q: 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?
Experiment: 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.
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