PIGQ (also known as GPI1 or PIG-Q) is a non-catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex, the multi-protein enzyme that catalyses the first, committed step of glycosylphosphatidylinositol (GPI) anchor biosynthesis: transfer of N-acetylglucosamine from UDP-GlcNAc onto phosphatidylinositol to form GlcNAc-phosphatidylinositol. Within this complex, PIGA is the catalytic subunit, while PIGQ is a required accessory subunit (together with PIGC, PIGH, PIGP, PIGY and DPM2) that stabilises the complex and supports its activity; PIGQ itself has no independent enzymatic activity. It is a multi-pass integral membrane protein of the endoplasmic reticulum membrane, where the GPI-GnT complex assembles and acts. Biallelic loss-of-function variants in PIGQ cause multiple congenital anomalies-hypotonia-seizures syndrome 4 (MCAHS4), an autosomal-recessive inherited GPI-deficiency disorder presenting as a developmental and epileptic encephalopathy with refractory neonatal seizures, severe global developmental delay, dysmorphism and skeletal, renal and ophthalmic anomalies.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing PIGQ in the endoplasmic reticulum. This is correct: the GPI-GnT complex containing PIGQ was biochemically shown to be an ER-membrane complex (PMID:9463366). ER is a core location, though the more specific ER membrane term (GO:0005789, below) better captures the localization of this multi-pass membrane protein. Reason: Consistent with experimental localization of the GPI-GnT complex to the ER membrane and conserved across orthologs. Supporting Evidence: PMID:9463366 four mammalian gene products form a protein complex in the endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to GPI anchor biosynthetic process. This is the core biological process for PIGQ: as a subunit of the GPI-GnT complex it participates in the first step of GPI biosynthesis, and the mammalian GPI1 protein functionally rescues yeast gpi1 mutants defective in this process (PMID:9729469). Reason: Core, well-supported and phylogenetically conserved biological role. Supporting Evidence: PMID:9729469 the mammalian GPI1 homologues can rescue haploids file:human/PIGQ/PIGQ-uniprot.txt participates in the first step of GPI |
| GO:0006506 GPI anchor biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (InterPro IPR007720 PigQ/GPI1 signature plus UniPathway) to GPI anchor biosynthetic process. The InterPro-to-GO mapping is accurate for this family-defining domain and agrees with the experimental and phylogenetic annotations to the same term. Reason: Correct family-level electronic inference, concordant with experimental evidence for the same process. Supporting Evidence: file:human/PIGQ/PIGQ-uniprot.txt participates in the first step of GPI |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Electronic annotation to the generic term membrane (from UniProt SubCell SL-0162 / InterPro). PIGQ is indeed a multi-pass membrane protein, but the specific compartment is known experimentally to be the endoplasmic reticulum membrane (PMID:9463366; PMID:16162815). The generic membrane term is uninformative and should be replaced by the more specific ER membrane term. Reason: Too general; experimental evidence localizes PIGQ/the GPI-GnT complex specifically to the ER membrane, so GO:0005789 is the appropriate term. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/PIGQ/PIGQ-uniprot.txt Membrane PMID:9463366 four mammalian gene products form a protein complex in the endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:10944123 Initial enzyme for glycosylphosphatidylinositol biosynthesis... | MARK AS OVER ANNOTATED | Summary: IPI (IntAct) annotation recording binary interactions of PIGQ/GPI1 with DPM2 and PIGA. These are physiological partners within the GPI-GnT complex: DPM2 associates with GPI-GnT through interactions that include GPI1, and PIG-P associates with both PIG-A and GPI1 (PMID:10944123). The bare "protein binding" term is uninformative; the underlying biology is captured by part_of the GPI-GnT complex (GO:0000506). Reason: "Protein binding" (GO:0005515) is too generic to convey function; the documented interactions are with fellow GPI-GnT subunits and are better represented by complex membership. Retained (not removed) as an experimental interaction annotation. Supporting Evidence: PMID:10944123 DPM2, but not two other components of dolichol-phosphate-mannose synthase, associates with GPI-GnT through interactions with PIG-A, PIG-C and GPI1 PMID:10944123 PIG-P, a 134-amino acid protein having two hydrophobic domains, associates with PIG-A and GPI1 |
| GO:0005515 protein binding | IPI PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | MARK AS OVER ANNOTATED | Summary: IPI (IntAct) annotation recording interaction of PIGQ with PIGA, a co-subunit of the GPI-GnT complex characterized in this study (PMID:16162815). As above, "protein binding" is uninformative and the interaction reflects assembly of the GPI-GnT complex (GO:0000506). Reason: Generic MF term; the interaction is with a fellow complex subunit and is better captured by GPI-GnT complex membership. Retained as an experimental interaction annotation. Supporting Evidence: PMID:16162815 Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by an unusually complex GPI-N-acetylglucosaminyltransferase (GPI-GnT) consisting of at least six proteins |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI (IntAct) annotation from the BioPlex 3.0 proteome-scale AP-MS interactome (PMID:33961781), recording interaction of PIGQ with PIGH, a GPI-GnT subunit. High-throughput; "protein binding" is uninformative and the interaction is consistent with GPI-GnT complex membership (GO:0000506). Reason: Generic MF term from a high-throughput interactome screen; the partner is a fellow complex subunit, better represented by complex membership. Retained as an experimental interaction annotation. Supporting Evidence: PMID:33961781 BioPlex 3.0, results from affinity purification of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 interactions among 14,586 proteins |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IPI (IntAct) annotation from a multimodal cell-map AP-MS study (PMID:40205054), recording interaction of PIGQ with PIGH. As with the other IPI annotations, "protein binding" is uninformative; the partner is a GPI-GnT subunit, consistent with complex membership (GO:0000506). Reason: Generic MF term from a high-throughput interactome/imaging study; the partner is a fellow complex subunit. Retained as an experimental interaction annotation. Supporting Evidence: PMID:40205054 a total of 36,842 interactions among 7,543 proteins |
| GO:0005515 protein binding | IPI PMID:9463366 The first step of glycosylphosphatidylinositol biosynthesis ... | MARK AS OVER ANNOTATED | Summary: IPI (IntAct) annotation recording interactions of PIGQ/GPI1 with PIGA, PIGC and PIGH. This is the foundational study defining the PIG-A/PIG-H/PIG-C/GPI1 complex in the ER membrane (PMID:9463366). The bare "protein binding" term is uninformative; the biology is captured by GPI-GnT complex membership (GO:0000506). Reason: Generic MF term; all partners are fellow GPI-GnT subunits and the interactions define the complex, which is better represented by GO:0000506. Retained as an experimental interaction annotation. Supporting Evidence: PMID:9463366 four mammalian gene products form a protein complex in the endoplasmic reticulum membrane |
| GO:0000506 glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex | IPI PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | ACCEPT | Summary: PIGQ is a component of the GPI-GnT complex. This ComplexPortal annotation (CPX-6502) records PIGQ as a subunit of the seven-component GPI-GnT complex (PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY, DPM2) characterized in PMID:16162815. This is a core cellular-component annotation for PIGQ. Reason: Directly supported by biochemical characterization of the GPI-GnT complex; PIGQ is an established subunit. Supporting Evidence: PMID:16162815 Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by an unusually complex GPI-N-acetylglucosaminyltransferase (GPI-GnT) consisting of at least six proteins file:human/PIGQ/PIGQ-uniprot.txt PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | ACCEPT | Summary: IDA annotation localizing PIGQ to the endoplasmic reticulum membrane, where the GPI-GnT complex assembles and acts. The GPI-GnT complex was biochemically shown to reside in the ER membrane (PMID:9463366), and PIGQ is a multi-pass ER-membrane protein. Core location. Reason: Specific, experimentally supported subcellular localization consistent with the complex's site of action. Supporting Evidence: PMID:9463366 four mammalian gene products form a protein complex in the endoplasmic reticulum membrane |
| GO:0000506 glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex | IDA PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | ACCEPT | Summary: IDA annotation (UniProt) recording PIGQ as part of the GPI-GnT complex, based on the biochemical characterization in PMID:16162815. Duplicate of the ComplexPortal complex annotation with direct experimental evidence; core cellular-component annotation. Reason: Directly supported by experimental characterization of the GPI-GnT complex; PIGQ is an established subunit. Supporting Evidence: PMID:16162815 A complex of six components was formed without PIG-Y file:human/PIGQ/PIGQ-uniprot.txt PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 |
| GO:0006506 GPI anchor biosynthetic process | IDA PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | ACCEPT | Summary: IDA annotation to GPI anchor biosynthetic process, from the study establishing the seven-component GPI-GnT complex that catalyses the first step of GPI biosynthesis (PMID:16162815). This is the core biological process for PIGQ. Reason: Core process, directly supported by characterization of the GPI-GnT complex to which PIGQ belongs. Supporting Evidence: PMID:16162815 Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by an unusually complex GPI-N-acetylglucosaminyltransferase (GPI-GnT) consisting of at least six proteins |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-162730 | ACCEPT | Summary: TAS annotation from Reactome localizing the GlcNAc-PI-forming reaction and its catalysing multimeric enzyme to the ER membrane. Concordant with the IDA ER-membrane annotation; core location. Reason: Consistent with experimental localization of the GPI-GnT complex to the ER membrane. Supporting Evidence: PMID:9463366 four mammalian gene products form a protein complex in the endoplasmic reticulum membrane |
| GO:0005975 carbohydrate metabolic process | TAS PMID:9729469 Human and mouse Gpi1p homologues restore glycosylphosphatidy... | MODIFY | Summary: TAS annotation to the very broad term carbohydrate metabolic process, based on the cloning/functional-complementation study of GPI1 (PMID:9729469). While technically true (the GPI-GnT reaction transfers a sugar), this term is far too general. The specific process is GPI anchor biosynthesis (formation of GlcNAc-PI), already captured by GO:0006506. Reason: Overly general; the informative and accurate term is GPI anchor biosynthetic process (GO:0006506), which describes the actual pathway PIGQ participates in. Proposed replacements: GPI anchor biosynthetic process Supporting Evidence: PMID:9729469 allow conclusions about a specific function for Gpi1p in stabilizing the enzymic complex |
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Download this section (compressed HTML)Q: What is the precise structural and mechanistic contribution of PIGQ within the GPI-GnT complex - does it act purely as a scaffolding/stabilising subunit, or does it also modulate substrate (phosphatidylinositol) selection or catalytic rate?
Experiment: Reconstitute the human GPI-GnT complex with and without PIGQ and measure GlcNAc-PI transferase activity and complex stability to quantify PIGQ's contribution to assembly versus catalysis.
Experiment: Determine a cryo-EM structure of the intact human GPI-GnT complex to define PIGQ's interfaces with PIGA (catalytic subunit), PIGC, PIGH, PIGP, PIGY and DPM2.
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