PIGA (phosphatidylinositol N-acetylglucosaminyltransferase subunit A) is the catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex, which catalyzes the first, committed step of glycosylphosphatidylinositol (GPI) anchor biosynthesis. PIGA transfers N-acetylglucosamine (GlcNAc) from UDP-N-acetylglucosamine (UDP-GlcNAc) onto phosphatidylinositol (PI) to form GlcNAc-PI (EC 2.4.1.198), a reaction occurring on the cytoplasmic face of the endoplasmic reticulum membrane. PIGA is a single-pass ER membrane protein with a large cytoplasmic catalytic domain (homologous to bacterial GlcNAc transferases, glycosyltransferase group 1 / GT4 family) and a small lumenal domain that mediates rough-ER localization. The GPI-GnT complex additionally contains PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2, with PIGA as the catalytic component. Somatic loss-of-function mutations of the X-linked PIGA gene in hematopoietic stem cells cause paroxysmal nocturnal hemoglobinuria (PNH), through loss of GPI-anchored complement regulators on blood cells; germline hypomorphic mutations cause X-linked recessive multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) and related neurodevelopmental disorders.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000506 glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex | IBA GO_REF:0000033 | ACCEPT | Summary: PIGA is a subunit of the GPI-GnT complex. This phylogenetically inferred complex membership is directly supported by experimental studies of the human complex and is a core aspect of PIGA biology. Reason: PIGA is the catalytic subunit of the GPI-GnT complex, which comprises at least PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2. The IBA call is corroborated by direct experimental identification of the human complex. Supporting Evidence: PMID:8900170 PIG-A and PIG-H are subunits of the GPI GlcNAc transferase that transfers GlcNAc to PI on the cytoplasmic side of the ER. 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: PIGA catalyzes the first, committed step of GPI anchor biosynthesis, so involvement in the GPI anchor biosynthetic process is a core biological process annotation. Reason: The catalytic first step (GlcNAc transfer to PI) initiates the GPI biosynthesis pathway. This is well established experimentally and consistent with the phylogenetic inference. Supporting Evidence: PMID:9463366 Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). |
| GO:0017176 phosphatidylinositol N-acetylglucosaminyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the exact, correct molecular function of PIGA - the catalytic subunit that transfers GlcNAc from UDP-GlcNAc to phosphatidylinositol (EC 2.4.1.198). Reason: PIGA is the catalytic component of the GPI-GnT enzyme; this specific transferase activity is the core molecular function and is directly supported by biochemistry. Supporting Evidence: PMID:9463366 The protein complex had GPI-GlcNAc transferase (GPI-GnT) activity in vitro. PMID:16162815 binding directly to the catalytic subunit PIG-A. |
| GO:0000506 glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic annotation of GPI-GnT complex membership (via the PIG-A/GPI3 signature IPR039507). Correct and consistent with experimental data. Reason: The IEA mapping from the PIG-A/GPI3 InterPro entry to the GPI-GnT complex is biologically correct; PIGA is an experimentally verified complex member. Supporting Evidence: PMID:8900170 PIG-A and PIG-H are subunits of the GPI GlcNAc transferase that transfers GlcNAc to PI on the cytoplasmic side of the ER. |
| GO:0006506 GPI anchor biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (InterPro/UniPathway) annotation to the GPI anchor biosynthetic process, matching the experimentally established role of PIGA. Reason: The pathway mapping (UPA00196 GPI-anchor biosynthesis) is correct; PIGA initiates this pathway. Supporting Evidence: PMID:9463366 Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). |
| GO:0016757 glycosyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic glycosyltransferase activity from the InterPro glycosyltransferase family 1 domain (IPR001296). Correct but a broad parent of the specific PIGA activity. Reason: This term is a general ancestor of the specific and experimentally supported GO:0017176 (phosphatidylinositol N-acetylglucosaminyltransferase activity), which is annotated separately. The generic term is not informative for PIGA's core function. Supporting Evidence: PMID:9463366 The protein complex had GPI-GlcNAc transferase (GPI-GnT) activity in vitro. |
| GO:0017176 phosphatidylinositol N-acetylglucosaminyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of the specific catalytic activity based on the RHEA/EC mapping (RHEA:14789, EC 2.4.1.198). This is the correct core molecular function. Reason: The EC/RHEA-derived assignment matches the experimentally established catalytic activity of PIGA and is the specific, informative molecular function term. 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/PIGA/PIGA-uniprot.txt EC=2.4.1.198 |
| GO:0030867 rough endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location keyword mapping to rough ER membrane. Correct and consistent with experimental localization data. Reason: PIGA localizes to the rough ER membrane; this specific location is experimentally verified (the small lumenal domain targets it to the rough ER). Supporting Evidence: PMID:8900170 part of the small lumenal domain of PIG-A plays an essential functional role in targeting itself to the rough ER. |
| GO:0005515 protein binding | IPI PMID:10944123 Initial enzyme for glycosylphosphatidylinositol biosynthesis... | MARK AS OVER ANNOTATED | Summary: IntAct-curated binary interactions of PIGA with GPI-GnT complex components (DPM2/O94777, PIGP/P57054, PIGH/Q14442, PIGQ/Q9BRB3). These reflect PIGA's role as a scaffolding/catalytic member of the GPI-GnT complex. Reason: The generic 'protein binding' term is uninformative. The underlying interactions are real and are the physical basis of the GPI-GnT complex, which is captured by the specific GO:0000506 (GPI-GnT complex) annotation. Per curation guidelines the bare protein binding IPI is not retained as a core function. Supporting Evidence: PMID:10944123 PIG-P, a 134-amino acid protein having two hydrophobic domains, associates with PIG-A and GPI1. 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. |
| GO:0005515 protein binding | IPI PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interactions of PIGA with GPI-GnT complex components including the directly associated regulatory subunit PIGY (Q3MUY2), plus DPM2, PIGP, PIGH, PIGQ. Real interactions underpinning complex assembly. Reason: Bare 'protein binding' is uninformative and is subsumed by the specific GPI-GnT complex (GO:0000506) annotation. The interactions themselves are genuine. Supporting Evidence: PMID:16162815 PIG-Y appeared to be directly associated with PIG-A. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput BioPlex 3.0 AP-MS interactions of PIGA (recovering PIGP and PIGH). Consistent with GPI-GnT complex membership but low information content. Reason: Generic 'protein binding' from a proteome-scale AP-MS screen; not a core function term. The recovered partners are GPI-GnT complex members captured by GO:0000506. Supporting Evidence: PMID:33961781 BioPlex suggests function, localization, and complex membership for thousands of proteins. |
| GO:0005515 protein binding | IPI PMID:8900170 PIG-A and PIG-H, which participate in glycosylphosphatidylin... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction of PIGA with PIGH (Q14442), the earliest characterized binary interaction within the GPI-GnT complex. Reason: The PIGA-PIGH interaction is real and foundational to the complex, but the generic 'protein binding' term is uninformative and is captured by the specific GPI-GnT complex (GO:0000506) annotation. Supporting Evidence: PMID:8900170 they form a protein complex. |
| GO:0005515 protein binding | IPI PMID:9463366 The first step of glycosylphosphatidylinositol biosynthesis ... | MARK AS OVER ANNOTATED | Summary: IntAct-curated interaction of PIGA with PIGQ/GPI1 (Q9BRB3), a component of the four-subunit GPI-GnT complex characterized in this study. Reason: Real interaction within the GPI-GnT complex, but the generic 'protein binding' term is uninformative and subsumed by GO:0000506 (GPI-GnT complex). Supporting Evidence: PMID:9463366 four mammalian gene products form a protein complex in the endoplasmic reticulum membrane. |
| GO:0006506 GPI anchor biosynthetic process | TAS Reactome:R-HSA-162710 | ACCEPT | Summary: Reactome traceable-author-statement placing PIGA in the GPI synthesis pathway. Matches PIGA's established role initiating GPI anchor biosynthesis. Reason: PIGA catalyzes the first reaction of GPI anchor biosynthesis; the Reactome pathway assignment is correct and core. Supporting Evidence: PMID:9463366 Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). |
| GO:0030867 rough endoplasmic reticulum membrane | EXP PMID:8900170 PIG-A and PIG-H, which participate in glycosylphosphatidylin... | ACCEPT | Summary: Experimental demonstration that PIGA is an ER transmembrane protein localizing to the rough ER, with its small lumenal domain required for rough-ER targeting. Reason: Directly supported by experimental localization/topology work; the rough ER membrane is a verified, specific location for PIGA. Supporting Evidence: PMID:8900170 PIG-A is an ER transmembrane protein with a large cytoplasmic domain that has homology to a bacterial GlcNAc transferase and a small lumenal domain. PMID:8900170 part of the small lumenal domain of PIG-A plays an essential functional role in targeting itself to the rough ER. |
| GO:0000506 glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex | IPI PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | ACCEPT | Summary: ComplexPortal (CPX-6502) assertion of PIGA as part of the GPI-GnT complex, based on the study identifying the seven-component complex including PIGY. Reason: PIGA is an experimentally established member (catalytic subunit) of the GPI-GnT complex; complex membership is a core 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:0005789 endoplasmic reticulum membrane | IDA PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | ACCEPT | Summary: Direct-assay localization of PIGA to the ER membrane, where the GPI-GnT complex assembles and functions. Reason: The ER membrane is the verified site of PIGA action and GPI-GnT complex assembly; this is a core cellular component annotation. Supporting Evidence: PMID:9463366 four mammalian gene products form a protein complex in the endoplasmic reticulum membrane. |
| GO:0008194 UDP-glycosyltransferase activity | TAS Reactome:R-HSA-162730 | MODIFY | Summary: Reactome describes the reaction as using the UDP-sugar donor UDP-GlcNAc. The term correctly captures the UDP-sugar donor class but is less specific than the exact enzyme activity. Reason: UDP-glycosyltransferase activity is a broad donor-class term. The specific, experimentally supported activity is phosphatidylinositol N-acetylglucosaminyltransferase activity (GO:0017176, EC 2.4.1.198), which uses UDP-GlcNAc as donor and PI as acceptor. Proposed replacements: phosphatidylinositol N-acetylglucosaminyltransferase activity Supporting Evidence: PMID:9463366 Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput identification of PIGA in an NK-cell membrane proteome. Only confirms membrane association without specifying the organelle. Reason: The 'membrane' term is a very general location from a proteome-scale study; PIGA's informative location is the ER membrane (GO:0005789 / GO:0030867), which is annotated separately with direct evidence. Supporting Evidence: PMID:19946888 approximately 40% of the identified proteins were predicted as plausible membrane proteins. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-162730 | ACCEPT | Summary: Reactome traceable-author-statement placing the GlcNAc-PI synthesis reaction (and PIGA) at the ER membrane. Consistent with direct experimental data. Reason: The ER membrane is the verified site of the PIGA-catalyzed reaction; a core cellular component annotation. Supporting Evidence: PMID:8900170 PIG-A is an ER transmembrane protein with a large cytoplasmic domain that has homology to a bacterial GlcNAc transferase and a small lumenal domain. |
| GO:0000506 glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex | IDA PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | ACCEPT | Summary: Direct-assay identification of PIGA as a component of the seven-subunit GPI-GnT complex (adding PIGY as the seventh component directly associated with PIGA). Reason: Experimentally established core complex membership; PIGA is the catalytic subunit. Supporting Evidence: PMID:16162815 PIG-Y appeared to be directly associated with PIG-A. |
| GO:0017176 phosphatidylinositol N-acetylglucosaminyltransferase activity | TAS PMID:16162815 The initial enzyme for glycosylphosphatidylinositol biosynth... | ACCEPT | Summary: Traceable-author-statement of PIGA's phosphatidylinositol N-acetylglucosaminyltransferase activity, from the study establishing catalytic activity and the seven-component complex. Reason: This is the specific, experimentally supported core molecular function of PIGA (catalytic subunit; EC 2.4.1.198). 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. |
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)