Affinage

PIGP

Phosphatidylinositol N-acetylglucosaminyltransferase subunit P · UniProt P57054

Length
158 aa
Mass
18.1 kDa
Annotated
2026-06-10
27 papers in source corpus 8 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIGP encodes an essential subunit of the GPI-N-acetylglucosaminyltransferase (GPI-GnT) complex, which catalyzes the first committed step of glycosylphosphatidylinositol (GPI) anchor biosynthesis at the ER membrane by transferring N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol (PMID:10944123). Within this complex PIGP physically associates with PIG-A and GPI1, and cells lacking PIGP are rendered GPI-anchor negative, defining PIGP as an indispensable structural component rather than a regulatory one—a role distinct from DPM2, which associates with other complex subunits and enhances enzyme activity without binding PIGP directly (PMID:10944123). The essential, conserved function is corroborated by the yeast and fungal homologs, which associate with the GPI2 subunit, are required for in vitro GPI-GlcNAc transferase activity, and whose loss produces cell wall and GPI synthesis defects (PMID:16278447, PMID:19421754). In humans, biallelic loss-of-function mutations in PIGP reduce surface expression of GPI-anchored proteins, and reintroduction of wild-type PIGP rescues this deficit, causing an inherited GPI deficiency presenting as developmental and epileptic encephalopathy (PMID:28334793, PMID:34750615).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 High

    Established that PIGP is a bona fide, essential subunit of the GPI-GnT complex rather than an accessory factor, defining the molecular machine that initiates GPI anchor synthesis.

    Evidence Co-immunoprecipitation with PIG-A and GPI1, plus a GPI-anchor-negative loss-of-function cell line and complementation

    PMID:10944123

    Open questions at the time
    • Catalytic contribution of PIGP versus its scaffolding role within the complex not resolved
    • No structure of the assembled complex
  2. 2000 Medium

    Distinguished PIGP's essential structural role from regulatory inputs by showing DPM2 enhances GPI-GnT activity ~3-fold via PIG-A, PIG-C, and GPI1 but not through PIGP.

    Evidence Co-immunoprecipitation and in vitro enzyme activity assay

    PMID:10944123

    Open questions at the time
    • Mechanism by which DPM2 enhances activity not defined
    • Whether regulation occurs in human cells the same way as in vitro untested
  3. 2005 High

    Confirmed functional conservation by showing the yeast homolog Gpi19p is an essential GPI-GlcNAc transferase subunit with defined ER membrane topology, linking GPI synthesis to cell wall and Ras-pathway phenotypes.

    Evidence Co-IP with Gpi2, in vitro enzyme activity assay, topology analysis, and temperature-sensitive mutant phenotyping in S. cerevisiae

    PMID:16278447

    Open questions at the time
    • Human PIGP membrane topology not directly mapped
    • Connection between GPI deficiency and Ras hyperactivity mechanistically unexplained
  4. 2009 Medium

    Connected loss of PIGP function to downstream secretory consequences by showing fungal pigP mutants have decreased GPI synthesis and aberrant secretion of a normally membrane-anchored protease.

    Evidence Mutant analysis with GPI synthesis measurement and protein secretion assay in Aspergillus nidulans

    PMID:19421754

    Open questions at the time
    • Findings in filamentous fungus may not transfer to human cell biology
    • Specific anchored substrates affected in humans not enumerated
  5. 2010 Medium

    Extended conservation and demonstrated gene-dosage sensitivity, showing the Candida homolog is essential and that even partial reduction produces cell wall, drug-sensitivity, and morphogenesis defects.

    Evidence Cross-species complementation and conditional null (MET3 promoter) phenotyping in Candida albicans

    PMID:20576690

    Open questions at the time
    • Whether dosage sensitivity applies to human heterozygotes untested here
    • Single lab
  6. 2017 Medium

    Established PIGP as a human disease gene by linking biallelic mutations to reduced GPI-anchored surface protein levels and demonstrating rescue by wild-type PIGP.

    Evidence Patient cell functional study, flow cytometry of GPI-anchored proteins, and wild-type PIGP rescue

    PMID:28334793

    Open questions at the time
    • Genotype-phenotype correlation across mutation types not established
    • Tissue-specific effects of GPI deficiency not addressed
  7. 2019 Medium

    Independently replicated the human requirement for PIGP in a second family, reinforcing the causal link between PIGP loss and GPI-anchored protein deficiency.

    Evidence Flow cytometry of GPI-anchored proteins on patient granulocytes

    PMID:31139695

    Open questions at the time
    • Single method
    • No mechanistic dissection beyond surface marker quantification
  8. 2020 Medium

    Identified a clinically usable functional readout by establishing reduced granulocyte CD16 as a marker of PIGP-related inherited GPI deficiency.

    Evidence Flow cytometry of CD16 on patient granulocytes from a large family

    PMID:32042915

    Open questions at the time
    • Predicted impaired functionality of elongated mutant protein not biochemically confirmed
    • Single method
  9. 2021 Medium

    Provided direct causal proof in engineered human cells that PIGP function is required for GPI anchor surface display, with knock-in correction restoring the anchor.

    Evidence CRISPR/Cas9 allele deletion plus truncation, flow cytometry of GPI anchors, and targeted knock-in rescue

    PMID:34750615

    Open questions at the time
    • Stoichiometry and assembly order of PIGP within the human GPI-GnT complex unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PIGP contributes structurally or mechanistically to GPI-GnT catalysis—its precise position, stoichiometry, and topology within the human complex—remains unresolved.
  • No high-resolution structure of the human GPI-GnT complex
  • Catalytic versus scaffolding contribution of PIGP undefined
  • Regulatory inputs governing complex activity in human cells uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 2
Partners
GPI1PIGA
Complex memberships
GPI-N-acetylglucosaminyltransferase (GPI-GnT)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PIGP (PIG-P) is an essential component of GPI-N-acetylglucosaminyltransferase (GPI-GnT), the enzyme that initiates GPI anchor biosynthesis by transferring N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol. PIG-P associates with PIG-A and GPI1 within the complex, and cells lacking PIG-P are GPI-anchor negative. Co-immunoprecipitation, cell-based complementation assay, GPI-anchor negative cell line generation The EMBO journal High 10944123
2000 DPM2, a regulator of dolichol-phosphate-mannose synthase, associates with GPI-GnT through interactions with PIG-A, PIG-C, and GPI1 (not directly with PIG-P), and enhances GPI-GnT enzyme activity approximately 3-fold, indicating a regulatory role distinct from PIGP's essential structural role. Co-immunoprecipitation, in vitro enzyme activity assay The EMBO journal Medium 10944123
2005 Gpi19p, the S. cerevisiae homolog of human PIG-P, is an essential subunit of the yeast GPI-GlcNAc transferase complex. It associates with the Gpi2 subunit in vivo, is required for GPI-GlcNAc transferase activity in vitro, and has a defined topology within the ER membrane. Temperature-sensitive gpi19 mutants display cell wall defects and hyperactive Ras phenotypes. Co-immunoprecipitation, in vitro enzyme activity assay, topology analysis, temperature-sensitive mutant phenotypic analysis Eukaryotic cell High 16278447
2010 CaGpi19p, the Candida albicans homolog of PIG-P, is the functional equivalent of S. cerevisiae Gpi19p and is essential for GPI anchor biosynthesis. An N-terminal truncation mutant of CaGpi19p complements a conditionally lethal S. cerevisiae gpi19 mutant. Repression of CaGPI19 causes growth defects, cell wall biogenesis aberrations, azole sensitivity, and hyperfilamentation, with a gene dosage effect observed in heterozygotes. Cross-species complementation assay, conditional null mutant (MET3 promoter control), phenotypic analysis Microbiology (Reading, England) Medium 20576690
2009 The Aspergillus nidulans pigP gene encodes a subunit of GPI-GnT; pigP mutants have significantly decreased GPI synthesis, display a 'button' phenotype with hyperbranched hyphae and impaired septation, and aberrantly secrete a 33-kDa alkaline serine protease into the medium, establishing PIGP's role in GPI-dependent protein membrane anchoring and secretion. Mutant analysis, GPI synthesis measurement, phenotypic characterization, protein secretion assay Current genetics Medium 19421754
2017 Compound heterozygous mutations in human PIGP (c.74T>C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34) cause reduced PIGP mRNA levels and reduced GPI-anchored cell surface proteins. Wild-type PIGP expression rescued GPI-anchored protein levels in patient cells, confirming PIGP's essential role in the first step of GPI anchor biosynthesis in humans. Patient cell functional study, flow cytometry of GPI-anchored proteins, exogenous wild-type PIGP rescue experiment Human molecular genetics Medium 28334793
2019 A homozygous frameshift mutation (c.456delA;p.Glu153Asnfs*34) in PIGP causes reduced expression of GPI-anchored proteins on patient granulocytes, as confirmed by flow cytometry, independently replicating that PIGP is required for GPI anchor biosynthesis in humans. Flow cytometry of GPI-anchored proteins on patient granulocytes Annals of clinical and translational neurology Medium 31139695
2020 A homozygous PIGP frameshift variant (c.384del) results in a longer-than-wild-type protein predicted to have impaired functionality, and is associated with reduced expression of the GPI-anchored protein CD16 on granulocyte membranes, establishing CD16 as a functional marker for PIGP-related inherited GPI deficiency. Flow cytometry of GPI-anchored protein CD16 on patient granulocytes Neurology. Genetics Medium 32042915
2021 PIGP is an autosomal gene essential for GPI-anchor biosynthesis; deletion of one PIGP allele followed by introduction of a truncating mutation in the other abolished GPI anchor display on the cell membrane, as detected by flow cytometry. This was rescued by correction of the PIGP mutation via targeted knock-in, directly demonstrating that PIGP function is required for GPI anchor surface expression. CRISPR/Cas9-based PIGP allele deletion, flow cytometry of GPI anchors, targeted knock-in rescue Bioscience reports Medium 34750615

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Analysis of the expression patterns, subcellular localisations and interaction partners of Drosophila proteins using a pigP protein trap library. Development (Cambridge, England) 130 25294943
2008 The crystal structure of Desulfovibrio vulgaris dissimilatory sulfite reductase bound to DsrC provides novel insights into the mechanism of sulfate respiration. The Journal of biological chemistry 125 18829451
2014 The "bacterial heterodisulfide" DsrC is a key protein in dissimilatory sulfur metabolism. Biochimica et biophysica acta 123 24662917
2000 Initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-P and is regulated by DPM2. The EMBO journal 110 10944123
2012 Cytoplasmic sulfurtransferases in the purple sulfur bacterium Allochromatium vinosum: evidence for sulfur transfer from DsrEFH to DsrC. PloS one 55 22815818
2010 PigS and PigP regulate prodigiosin biosynthesis in Serratia via differential control of divergent operons, which include predicted transporters of sulfur-containing molecules. Journal of bacteriology 55 21183667
2013 A Serratia marcescens PigP homolog controls prodigiosin biosynthesis, swarming motility and hemolysis and is regulated by cAMP-CRP and HexS. PloS one 52 23469212
2008 Allochromatium vinosum DsrC: solution-state NMR structure, redox properties, and interaction with DsrEFH, a protein essential for purple sulfur bacterial sulfur oxidation. Journal of molecular biology 39 18656485
2017 Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy. Human molecular genetics 37 28334793
2001 Solution structure of Pyrobaculum aerophilum DsrC, an archaeal homologue of the gamma subunit of dissimilatory sulfite reductase. European journal of biochemistry 33 11722571
2010 The Candida albicans homologue of PIG-P, CaGpi19p: gene dosage and role in growth and filamentation. Microbiology (Reading, England) 30 20576690
2004 Protein levels of genes encoded on chromosome 21 in fetal Down Syndrome brain (Part V): overexpression of phosphatidyl-inositol-glycan class P protein (DSCR5). Amino acids 27 15221505
2000 Isolation of two novel genes, DSCR5 and DSCR6, from Down syndrome critical region on human chromosome 21q22.2. Biochemical and biophysical research communications 26 10814524
2005 Gpi19, the Saccharomyces cerevisiae homologue of mammalian PIG-P, is a subunit of the initial enzyme for glycosylphosphatidylinositol anchor biosynthesis. Eukaryotic cell 23 16278447
2020 Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations. Neurology. Genetics 20 32042915
2013 Redox states of Desulfovibrio vulgaris DsrC, a key protein in dissimilatory sulfite reduction. Biochemical and biophysical research communications 14 24211572
2016 Fractionation of sulfur and hydrogen isotopes in Desulfovibrio vulgaris with perturbed DsrC expression. FEMS microbiology letters 12 27702753
2008 Purification, crystallization and preliminary crystallographic analysis of a dissimilatory DsrAB sulfite reductase in complex with DsrC. Journal of structural biology 11 18706503
2019 Biallelic mutations in PIGP cause developmental and epileptic encephalopathy. Annals of clinical and translational neurology 7 31139695
2009 The Aspergillus nidulans pigP gene encodes a subunit of GPI-N-acetylglucosaminyltransferase which influences filamentation and protein secretion. Current genetics 6 19421754
2001 Molecular cloning and characterization of a gene expressed in mouse developing tongue, mDscr5 gene, a homolog of human DSCR5 (Down syndrome Critical Region gene 5). Mammalian genome : official journal of the International Mammalian Genome Society 6 11331941
2023 DsrC is involved in fermentative growth and interacts directly with the FlxABCD-HdrABC complex in Desulfovibrio vulgaris Hildenborough. Environmental microbiology 5 36602077
2019 Proteomic and Isotopic Response of Desulfovibrio vulgaris to DsrC Perturbation. Frontiers in microbiology 5 31031715
2000 A novel gene, DSCR5, from the distal Down syndrome critical region on chromosome 21q22.2. DNA research : an international journal for rapid publication of reports on genes and genomes 5 10907851
2023 Expanding the phenotype of PIGP deficiency to multiple congenital anomalies-hypotonia-seizures syndrome. Clinical genetics 3 37125481
2019 Structural study to analyze the DNA-binding properties of DsrC protein from the dsr operon of sulfur-oxidizing bacterium Allochromatium vinosum. Journal of molecular modeling 3 30798412
2021 Flow cytometry-based quantification of targeted knock-in events in human cell lines using a GPI-anchor biosynthesis gene PIGP. Bioscience reports 2 34750615

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