PIGG is the catalytic subunit of the glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase II complex (GPI-ET-II; also known as GPI7/hGPI7). During GPI-anchor biosynthesis in the endoplasmic reticulum, PIGG transfers an ethanolamine phosphate (EtNP), donated by phosphatidylethanolamine, onto the 6-OH of the second alpha-1,6-linked mannose of the GPI intermediate (the H7-to-H8 conversion). This second-mannose EtNP is a side-branch modification that is normally removed shortly after the anchor is transferred to protein. PIGG acts together with the accessory subunit PIGF, which stabilizes it, and competes with PIGO (which adds EtNP to the third mannose) for the shared PIGF stabilizer. PIGG is a multi-pass endoplasmic reticulum membrane protein with a large lumenal alkaline-phosphatase-like catalytic domain. Biallelic loss-of-function variants cause an inherited GPI-deficiency disorder characterized by intellectual disability/developmental delay, early-onset seizures, hypotonia, and cerebellar atrophy; genetic variation in PIGG also defines the Emm blood group system.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PIGG is a multi-pass endoplasmic reticulum membrane protein and carries out its EtNP-transferase reaction in the ER during GPI-anchor biosynthesis. The phylogenetic (IBA) location call is consistent with direct experimental localization and with the UniProt subcellular location. Reason: Correct compartment for the site of PIGG action, corroborated by experimental localization (PMID:15632136) and UniProt. Supporting Evidence: file:human/PIGG/PIGG-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the core molecular function of PIGG - transfer of ethanolamine phosphate from phosphatidylethanolamine to the second mannose of the GPI intermediate. The IBA call at this term is well supported by the human experimental data and the conserved yeast ortholog Gpi7p. Reason: Represents the correct, specific catalytic activity of PIGG and is the core function; matches the current GOA term. Supporting Evidence: PMID:32156170 PIGG (initially termed GPI7) [67], catalytic subunits of GPI-ETII and GPI-ETIII. Both PIGO and PIGG are stabilized by association with PIGF |
| GO:0006506 GPI anchor biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PIGG catalyzes one step (transfer of EtNP to the second mannose) of the glycosylphosphatidylinositol-anchor biosynthetic pathway. The IBA process call is well supported. Reason: Correct core biological process for this GPI-anchor biosynthetic enzyme. Supporting Evidence: PMID:34113002 is an ethanolamine phosphate transferase that catalyzes the modification of the second mannose of glycosylphosphatidylinositol (GPI) |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping from the UniProt subcellular location vocabulary (SL-0097, ER membrane), consistent with experimental localization of PIGG. Reason: Correct location, agrees with experimental evidence and UniProt curation. Supporting Evidence: file:human/PIGG/PIGG-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated inference (InterPro/UniPathway) that PIGG participates in GPI-anchor biosynthesis. This is correct and consistent with experimental data. Reason: Correct process; the InterPro/UniPathway mapping is sound for this GPI-ET family enzyme. Supporting Evidence: file:human/PIGG/PIGG-uniprot.txt PATHWAY: Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of the specific mannose-ethanolamine phosphotransferase activity, matching the experimentally established function. Reason: Correct specific molecular function; the InterPro2GO mapping is appropriate. Supporting Evidence: PMID:15632136 forms a protein complex with PIG-F and is involved in the H7-to-H8 conversion |
| GO:0005515 protein binding | IPI PMID:23864651 The identification of novel proteins that interact with the ... | MARK AS OVER ANNOTATED | Summary: An IntAct-derived interaction annotation linking PIGG to the GLP-1 receptor (GLP1R, P43220), from a study screening for novel GLP1R interactors. Bare "protein binding" is uninformative and this interaction is not part of PIGG's characterized catalytic function in GPI-anchor biosynthesis; there is no evidence it reflects a physiological binding activity of PIGG. Reason: Uninformative generic "protein binding" from a high-throughput interactome screen; per curation guidelines this term does not convey PIGG's actual molecular function and the GLP1R interaction is not an established functional partner. Supporting Evidence: file:human/PIGG/PIGG-uniprot.txt Q5H8A4; P43220: GLP1R; NbExp=2; IntAct=EBI-11724298, EBI-7466542 |
| GO:0006506 GPI anchor biosynthetic process | TAS Reactome:R-HSA-162710 | ACCEPT | Summary: Reactome traceable assertion that PIGG participates in synthesis of GPI. Correct and consistent with the experimental and phylogenetic evidence. Reason: Correct core process from an authoritative pathway resource. Supporting Evidence: PMID:32156170 PIGG (initially termed GPI7) [67], catalytic subunits of GPI-ETII and GPI-ETIII. Both PIGO and PIGG are stabilized by association with PIGF |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IDA PMID:15632136 GPI7 is the second partner of PIG-F and involved in modifica... | ACCEPT | Summary: Direct experimental evidence (Shishioh et al. 2005) that human GPI7/PIGG, in complex with PIG-F, mediates the transfer of ethanolamine phosphate to the second mannose (H7-to-H8 conversion). This is the defining catalytic activity of PIGG. Reason: Experimentally demonstrated core molecular function; matches the current GOA term (GO:0051377; the older UniProt-DR term GO:0051267 is now obsolete). Supporting Evidence: PMID:15632136 an additional ethanolamine phosphate (EtNP) to the second mannose PMID:15632136 forms a protein complex with PIG-F and is involved in the H7-to-H8 conversion |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:15632136 GPI7 is the second partner of PIG-F and involved in modifica... | ACCEPT | Summary: Experimental localization of PIGG/hGPI7 to the endoplasmic reticulum membrane, where GPI-anchor biosynthesis occurs. Reason: Experimentally supported correct location of action. Supporting Evidence: file:human/PIGG/PIGG-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:32156170 Biosynthesis and biology of mammalian GPI-anchored proteins. | ACCEPT | Summary: Author-statement (review) localization to the ER membrane, consistent with the described role of PIGG as a multi-pass ER-membrane GPI-ET enzyme. Reason: Correct location; consistent with experimental data and the ComplexPortal GPI-ETII complex annotation. Supporting Evidence: PMID:32156170 Three GPI-ETs (PIGN, PIGO and PIGG) are also multiple transmembrane proteins bearing catalytic sites within the luminal regions |
| GO:0016740 transferase activity | IMP PMID:34113002 PIGG variant pathogenicity assessment reveals characteristic... | MODIFY | Summary: The variant-pathogenicity study measured PIGG enzymatic (EtNP-transferase) activity via restoration of GPI-AP expression in PIGO/PIGG double-knockout cells, showing that pathogenic variants abolish or reduce this activity. The generic parent "transferase activity" understates the specific, experimentally assayed function. Reason: Too general; the assay specifically measures PIGG's ethanolamine-phosphate transferase (mannose-ethanolamine phosphotransferase) activity, so it should be replaced by the specific molecular function term. Proposed replacements: mannose-ethanolamine phosphotransferase activity Supporting Evidence: PMID:34113002 ten variants had a null enzymatic activity PMID:34113002 is an ethanolamine phosphate transferase that catalyzes the modification of the second mannose of glycosylphosphatidylinositol (GPI) |
| GO:0016780 phosphotransferase activity, for other substituted phosphate groups | TAS Reactome:R-HSA-162742 | KEEP AS NON CORE | Summary: Reactome traceable assertion capturing PIGG's phosphotransferase (EtNP-transfer) reaction at a broader level. This is a correct parent of the specific mannose-ethanolamine phosphotransferase activity but is less informative than GO:0051377. Reason: Correct but non-core generic parent term from Reactome; the specific EtNP-transferase activity (GO:0051377) is the core function captured elsewhere. Supporting Evidence: PMID:15632136 an additional ethanolamine phosphate (EtNP) to the second mannose |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput mass-spectrometry detection of PIGG in an NK-cell membrane proteome. "Membrane" is an uninformative parent term; the specific and correct location for PIGG is the endoplasmic reticulum membrane. Reason: Uninformative high-level compartment from a bulk membrane-proteome study; the specific ER membrane term is better supported and captured by other annotations. 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-162742 | ACCEPT | Summary: Reactome traceable assertion placing PIGG's reaction at the ER membrane, consistent with all other localization evidence. Reason: Correct location from an authoritative pathway resource. Supporting Evidence: file:human/PIGG/PIGG-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | IDA PMID:15632136 GPI7 is the second partner of PIG-F and involved in modifica... | ACCEPT | Summary: Direct experimental localization of PIGG/hGPI7 to the endoplasmic reticulum (broader compartment consistent with the ER membrane annotations). Reason: Correct compartment, experimentally supported; a valid broader parent of endoplasmic reticulum membrane. Supporting Evidence: file:human/PIGG/PIGG-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IDA PMID:15632136 GPI7 is the second partner of PIG-F and involved in modifica... | ACCEPT | Summary: Direct experimental evidence that knockdown of hGPI7/PIGG blocks the H7-to-H8 conversion, placing PIGG within the GPI-anchor biosynthetic process. Reason: Experimentally supported involvement in the core GPI-anchor biosynthetic process. Supporting Evidence: PMID:15632136 forms a protein complex with PIG-F and is involved in the H7-to-H8 conversion |
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