PIGM is the catalytic subunit of GPI mannosyltransferase I (GPI-MT-I), the enzyme that transfers the first mannose, in an alpha-1,4 linkage, from dolichyl-phosphate-mannose (Dol-P-Man) onto the glucosaminyl-(acyl)phosphatidylinositol (GlcN-(acyl)PI) intermediate during glycosylphosphatidylinositol (GPI) anchor biosynthesis. It is a multi-pass endoplasmic reticulum membrane protein whose catalytic DXD motif faces the ER lumen, so this mannosylation step occurs on the lumenal side of the ER membrane. PIGM acts together with the stabilizing subunit PIGX to form the GPI-MT-I complex. Loss of PIGM function causes an inherited GPI deficiency (GPI biosynthesis defect); a hypomorphic PIGM promoter mutation is associated with portal and cerebral vein thrombosis and atypical absence seizures.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000030 mannosyltransferase activity | IBA GO_REF:0000033 | MODIFY | Summary: General mannosyltransferase activity, assigned by phylogenetic inference. This is correct but far less specific than PIGM's characterized activity (transfer of the first GPI mannose via an alpha-1,4 bond from Dol-P-Man), which is captured by GO:0180041. Reason: The annotation is in the right molecular-function branch but is too general. PIGM is a specific GPI alpha-1,4-mannosyltransferase (GPI-MT-I); the specific term GO:0180041 (also present in GOA with IDA support) should be preferred. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity Supporting Evidence: PMID:32156170 PIGM and PIGV are GPI-mannosyltransferase (MT) I and II, respectively |
| GO:1990529 glycosylphosphatidylinositol-mannosyltransferase I complex | IBA GO_REF:0000033 | ACCEPT | Summary: PIGM is part of the GPI-mannosyltransferase I complex, which in mammals comprises the catalytic subunit PIGM and the stabilizing subunit PIGX. This is the correct complex assignment for PIGM. Reason: The GPI-MT-I complex membership is well established; PIGM is its catalytic subunit and PIGX stabilizes it. Supporting Evidence: PMID:32156170 PIGM functions in association with PIGX, which stabilizes PIGM file:human/PIGM/PIGM-uniprot.txt complex that is composed of PIGM and PIGX |
| GO:0006506 GPI anchor biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PIGM catalyzes step 6 of GPI-anchor biosynthesis (addition of the first mannose), so involvement in the GPI anchor biosynthetic process is the core biological process for this gene. Reason: Well-supported core biological process; consistent with the experimental IDA annotation to the same term. Supporting Evidence: PMID:11226175 PIG-M transfers the first mannose to glycosylphosphatidylinositol on the lumenal |
| GO:0004376 GPI mannosyltransferase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based (IPR007704, PIG-M) electronic annotation to GPI mannosyltransferase activity. This is accurate for PIGM but less specific than the characterized dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity (GO:0180041). Reason: Correct branch and biologically accurate, but the specific characterized activity term (GO:0180041) is preferable as the representative molecular function. Proposed replacements: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity Supporting Evidence: PMID:11226175 PIG-M transfers the first mannose to glycosylphosphatidylinositol on the lumenal |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation from UniProt Subcellular Location mapping to ER membrane, consistent with the experimental IDA localization (PMID:11226175) and the multi-pass ER membrane topology. Reason: Correct localization, corroborated by experimental evidence. Supporting Evidence: file:human/PIGM/PIGM-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (InterPro/UniPathway) to GPI anchor biosynthetic process, redundant with and consistent with the IBA and IDA annotations to the same term. Reason: Correct core biological process; supported by experimental evidence. Supporting Evidence: PMID:11226175 PIG-M transfers the first mannose to glycosylphosphatidylinositol on the lumenal |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic membrane localization from InterPro. PIGM is a multi-pass ER membrane protein, so this is correct but uninformatively broad relative to the ER membrane annotation (GO:0005789). Reason: Not wrong, but subsumed by the more specific and experimentally supported GO:0005789 (endoplasmic reticulum membrane); the bare 'membrane' term adds little. Supporting Evidence: file:human/PIGM/PIGM-uniprot.txt Multi-pass membrane protein |
| GO:0051751 alpha-1,4-mannosyltransferase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based annotation to alpha-1,4-mannosyltransferase activity. PIGM does form an alpha-1,4 mannosidic bond, so this is accurate, but it is more general than the specific GPI substrate reaction (GO:0180041). Reason: Correct linkage-level activity but less specific than the characterized dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity; GO:0180041 is preferred. Proposed replacements: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity Supporting Evidence: file:human/PIGM/PIGM-uniprot.txt transfer of the first mannose, via an alpha-1,4 bond from a dolichol-phosphate-mannose |
| GO:0180041 dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based electronic annotation (RHEA:60500) to the specific catalytic activity of PIGM. This exactly matches the UniProt catalytic activity and the experimental IDA annotation to the same term, and is the representative molecular function of PIGM. Reason: This is the precise, correct molecular function of PIGM and is independently supported by experimental evidence (PMID:11226175) and the UniProt Rhea reaction. Supporting Evidence: PMID:11226175 PIG-M transfers the first mannose to glycosylphosphatidylinositol on the lumenal file:human/PIGM/PIGM-uniprot.txt transfer of the first mannose, via an alpha-1,4 bond from a dolichol-phosphate-mannose |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput AP-MS interaction (BioPlex 2.0) recording binding to STARD7 (UniProtKB:Q9NQZ5). 'Protein binding' is uninformative and the partner captured here is not the functional GPI-MT-I subunit (PIGX); STARD7 is a phosphatidylcholine transfer protein, so this is most likely an incidental proteome-scale co-purification. Reason: Bare 'protein binding' from a genome-scale interactome screen does not convey a specific molecular function and the STARD7 interaction is not the biologically characterized GPI-MT-I partnership; retained but flagged rather than removed, per policy on experimental IPIs. Supporting Evidence: file:human/PIGM/PIGM-uniprot.txt Q9NQZ5: STARD7; NbExp=2 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput AP-MS interaction (BioPlex 3.0) again recording binding to STARD7 (UniProtKB:Q9NQZ5). As with the BioPlex 2.0 annotation, 'protein binding' is uninformative and STARD7 is not the functional GPI-MT-I partner. Reason: Duplicate uninformative bare 'protein binding' from a proteome-scale interactome; does not represent a specific molecular function. Retained but flagged rather than removed, per policy on experimental IPIs. Supporting Evidence: file:human/PIGM/PIGM-uniprot.txt Q9NQZ5: STARD7; NbExp=2 |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:32156170 Biosynthesis and biology of mammalian GPI-anchored proteins. | ACCEPT | Summary: ComplexPortal (CPX-2697) assertion that PIGM localizes to the ER membrane, where GPI biosynthesis takes place. Consistent with experimental and electronic ER-membrane annotations. Reason: Correct localization; GPI is assembled on the ER membrane and PIGM is a multi-pass ER membrane protein. Supporting Evidence: PMID:32156170 PIGM and PIGV are GPI-mannosyltransferase (MT) I and II, respectively file:human/PIGM/PIGM-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:1990529 glycosylphosphatidylinositol-mannosyltransferase I complex | NAS PMID:32156170 Biosynthesis and biology of mammalian GPI-anchored proteins. | ACCEPT | Summary: ComplexPortal (CPX-2697) assertion of PIGM membership in the GPI-mannosyltransferase I complex (PIGM + PIGX). Correct and consistent with the IBA and ISS annotations to the same complex. Reason: Well-supported complex membership; PIGM is the catalytic subunit of GPI-MT-I. Supporting Evidence: PMID:32156170 PIGM functions in association with PIGX, which stabilizes PIGM |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:11226175 PIG-M transfers the first mannose to glycosylphosphatidylino... | ACCEPT | Summary: Direct experimental localization of PIG-M to the ER membrane; the catalytic DXD motif faces the ER lumen, showing that PIGM is an ER membrane protein acting on the lumenal side. Reason: Experimental (IDA) ER membrane localization, corroborated by the multi-pass ER membrane topology; this is the core localization. Supporting Evidence: PMID:11226175 PIG-M has a functionally important DXD motif, a characteristic of many file:human/PIGM/PIGM-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IDA PMID:11226175 PIG-M transfers the first mannose to glycosylphosphatidylino... | ACCEPT | Summary: Direct experimental demonstration that PIG-M is required for and catalyzes the addition of the first mannose in GPI biosynthesis (identified via a GPI-MT-I-defective human cell line rescued by PIG-M). This is the core biological process of PIGM. Reason: Strong experimental (IDA) support for the core GPI-anchor biosynthetic role. Supporting Evidence: PMID:11226175 PIG-M transfers the first mannose to glycosylphosphatidylinositol on the lumenal |
| GO:0180041 dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity | IDA PMID:11226175 PIG-M transfers the first mannose to glycosylphosphatidylino... | ACCEPT | Summary: Direct experimental evidence for the specific catalytic activity of PIG-M, transfer of the first mannose via an alpha-1,4 bond from Dol-P-Man to GlcN-(acyl)PI, on the lumenal side of the ER; mutation of the DXD motif (D49/D51) abolishes activity. This is the representative molecular function of PIGM. Reason: Precise, experimentally established (IDA) molecular function; the DXD-motif mutagenesis confirms catalytic requirement. Supporting Evidence: PMID:11226175 PIG-M has a functionally important DXD motif, a characteristic of many file:human/PIGM/PIGM-uniprot.txt transfer of the first mannose, via an alpha-1,4 bond from a dolichol-phosphate-mannose |
| GO:1990529 glycosylphosphatidylinositol-mannosyltransferase I complex | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (from mouse Pigm, UniProtKB:Q9EQY6) of membership in the GPI-MT-I complex. Consistent with the IBA and NAS annotations to the same complex. Reason: Correct complex membership, corroborated by orthology and by ComplexPortal. Supporting Evidence: file:human/PIGM/PIGM-uniprot.txt complex that is composed of PIGM and PIGX |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-162830 | ACCEPT | Summary: Reactome traceable assertion placing the PIG-M/PIG-X-catalyzed first-mannose addition (step 6 of GPI synthesis) at the lumenal surface of the ER membrane. Consistent with the experimental ER-membrane localization. Reason: Correct localization from an authoritative pathway resource; matches experimental evidence. Supporting Evidence: Reactome:R-HSA-162830 In the fifth step of GPI synthesis, a mannose residue is added to glucosaminyl-acyl-PI |
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Download this section (compressed HTML)Q: Does the STARD7 interaction captured in BioPlex have any physiological relevance to GPI-MT-I function or ER lipid supply, or is it an incidental proteome-scale co-purification?
Experiment: Structural determination of the human PIGM-PIGX GPI-MT-I complex to define the Dol-P-Man and GlcN-(acyl)PI binding sites and the role of the lumenal DXD motif.
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