Affinage

GP9

Platelet glycoprotein IX · UniProt P14770

Length
177 aa
Mass
19.0 kDa
Annotated
2026-06-10
31 papers in source corpus 16 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GP9 encodes GPIX, a transmembrane subunit of the platelet GPIb-IX-V von Willebrand factor receptor complex, where it is essential for assembly and surface expression of the entire complex (PMID:12100158, PMID:37416759). GPIX engages GPIbβ through a defined quaternary interface in which GPIbβ Tyr106 inserts into a pocket formed by GPIX loops b and c, an interface resolved by crystallography and validated by Bernard-Soulier mutations (A108P, P74R) that abolish GPIX surface expression (PMID:21908432). Proper biogenesis of GPIX depends on the integrity of its signal peptide for correct ER insertion (PMID:12100158) and on intramolecular and inter-subunit disulfide bonding, including the mature Cys8–Cys12 bond, whose disruption eliminates the complex from the platelet surface and impairs GPIbα–GPIbβ disulfide formation (PMID:11167791, PMID:11297032, PMID:14510954, PMID:17804902). GPIX is required for the native conformation and adhesive function of GPIbα: loss of GPIX prevents conformation-dependent antibody binding and ristocetin-induced agglutination (PMID:9886312), although a residual GPIbα/β heterodimer can assemble and support VWF and collagen adhesion independently of GPIX (PMID:7949089, PMID:23143686). Loss-of-function mutations in GP9 cause Bernard-Soulier syndrome type C through absence of the surface VWF receptor complex, with downstream consequences for megakaryopoiesis including a severe (96%) reduction in proplatelet formation and dysregulation of actin/tubulin folding pathways (PMID:37416759, PMID:41017962); lentiviral restoration of GPIX rescues surface complex expression and normalizes platelet size (PMID:37416759).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 Medium

    Established that GPIbβ and GPIX can assemble and reach the platelet surface partially independently of the GPIbα transmembrane and cytoplasmic regions, defining the modular nature of complex assembly.

    Evidence Biochemical and flow cytometric characterization of patient platelets carrying a truncating GPIbα Ser444stop mutation

    PMID:7949089

    Open questions at the time
    • Single patient case without cell reconstitution
    • Does not define the GPIX-GPIbβ contact directly
  2. 1998 Medium

    Showed that GPIX is required for proper GPIbα conformation and adhesive function, not merely surface presence, since GPIX loss left GPIbα present but non-functional.

    Evidence Patient platelet flow cytometry, conformation-dependent antibody binding, and ristocetin agglutination with a GPIX Leu40Pro mutation

    PMID:9886312

    Open questions at the time
    • No cell reconstitution
    • Mechanism linking GPIX to GPIbα conformation not resolved
  3. 1999 High

    Demonstrated reciprocal dependence between GPIbβ and GPIX for surface expression, framing the complex as an obligate co-assembly.

    Evidence Reciprocal functional rescue by wild-type vs mutant GPIbβ transfection in CHO/293T cells expressing GPIbα

    PMID:10216092

    Open questions at the time
    • Atomic interface not defined
    • Focused on GPIbβ rather than GPIX residues
  4. 2001 Medium

    Linked GPIX disulfide bonding (Cys8–Cys12) and a conserved Asn residue to both intramolecular folding and inter-subunit GPIbα–GPIbβ disulfide formation, implicating GPIX in oxidative assembly of the complex.

    Evidence Patient platelet biochemistry and sequencing of Cys8Arg and Asn45Ser BSS mutations, replicated across unrelated patients

    PMID:11167791 PMID:11297032 PMID:14510954 PMID:17804902

    Open questions at the time
    • Disulfide disruption inferred, not biochemically reconstituted
    • Single-case data for Cys8Arg
  5. 2002 High

    Identified the GPIX signal peptide hydrophobic core as essential for correct ER insertion and biogenesis of the entire GPIb-V-IX complex.

    Evidence Co-transfection of GPIX Leu7Pro with normal GPIbα/β in CHO cells recapitulating the patient phenotype

    PMID:12100158

    Open questions at the time
    • Step at which mistargeted GPIX is degraded not defined
  6. 2002 High

    Mapped the conformational GPIbβ region (cysteine knot, residues 1-14 and 15-32) required for interaction with GPIX, localizing the assembly contact on the GPIbβ side.

    Evidence N-terminal truncation and chimera mutants of GPIbβ with surface expression readout and epitope-mapping antibody

    PMID:12036872

    Open questions at the time
    • GPIX-side contact residues not yet defined
    • No structural model at this stage
  7. 2003 High

    Localized the drug-dependent (quinine) antibody epitope to the GPIX C-terminal extracellular region, identifying surface-exposed residues Arg110 and Gln115.

    Evidence Mouse/human GPIX chimeras and site-directed mutagenesis in CHO cells tested against patient sera

    PMID:12738668

    Open questions at the time
    • Relevance to assembly versus immunogenicity not separated
  8. 2011 High

    Resolved the atomic GPIbβ-GPIX quaternary interface, defining how GPIbβ Tyr106 docks into GPIX loops b/c and explaining BSS mutations that perturb this contact.

    Evidence X-ray crystallography of GPIbβ ectodomain and GPIbβ/GPIX chimera with mutagenesis and surface expression validation

    PMID:21908432

    Open questions at the time
    • Structure of full-length GPIX in the intact complex not solved
    • Stoichiometric arrangement with GPV not directly resolved
  9. 2012 Medium

    Established that GPIbα/β can form a functional adhesive complex independent of GPIX, refining which functions strictly require GPIX.

    Evidence Stable CHO-K1 expression and platelet adhesion/agglutination assays with a GPIX W127X nonsense mutation

    PMID:23143686

    Open questions at the time
    • Single lab
    • Reconciliation with GPIX requirement for GPIbα conformation not fully resolved
  10. 2019 Medium

    Confirmed GP9 as a causal gene for Bernard-Soulier-type macrothrombocytopenia in a non-human (canine) model, supporting cross-species conservation of GPIX function.

    Evidence Whole genome sequencing, genotyping and immunocytochemistry of a frameshift GP9 deletion in Cocker Spaniels

    PMID:31484196

    Open questions at the time
    • No in vitro reconstitution
    • Megakaryocyte-level mechanism not examined
  11. 2021 Medium

    Showed that cancer cells acquire GPIX (CD42a) by phagocytosing platelets and recycling the protein into their own membrane, indicating GPIX can mark tumor cells via platelet uptake.

    Evidence Confocal imaging, flow cytometry and dynamin inhibition in cancer cell lines with a non-cancerous control

    PMID:34592045

    Open questions at the time
    • Functional consequence of acquired GPIX on tumor cells unknown
    • Single lab
  12. 2023 High

    Demonstrated that GP9 is both necessary and sufficient for GPIb-IX-V surface localization and normal platelet size, enabling gene-therapy rescue of BSS phenotypes.

    Evidence CRISPR knockout and lentiviral GP9 rescue in megakaryoblastic lines, iPSC-derived platelets and patient HSCs with flow cytometry readouts

    PMID:37416759

    Open questions at the time
    • Durability and in vivo efficacy of gene therapy not addressed in this corpus
  13. 2025 Medium

    Defined megakaryocyte-intrinsic consequences of GPIX loss, quantifying a severe proplatelet defect and linking GPIX to RNA metabolism and actin/tubulin folding pathways during megakaryopoiesis.

    Evidence Homozygous GP9 deletion in imMKCL with proplatelet assays and staged RNA-seq plus patient platelet transcriptomics

    PMID:41017962

    Open questions at the time
    • Single lab/single study
    • Causal mechanism connecting GPIX loss to cytoskeletal-folding dysregulation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GPIX coordinates oxidative folding, ER insertion, and cytoskeletal/RNA pathways into a single biogenesis program remains unresolved.
  • No full-length structure of GPIX within the intact GPIb-IX-V complex
  • Causal chain from GPIX loss to actin/tubulin folding dysregulation undefined
  • Mechanism of GPIX-dependent GPIbα conformation not biochemically reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0001618 virus receptor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-109582 Hemostasis 3 R-HSA-392499 Metabolism of proteins 3
Partners
GP1BAGP1BBGP5
Complex memberships
GPIb-IX-V complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 GPIbβ interaction with GPIX is essential for surface expression of GPIbα: a frameshift mutation in GPIbβ (Ala80 codon deletion) caused absence of GPIX on the platelet surface, and transfection of wild-type GPIbβ into CHO cells stably expressing GPIbα rescued GPIX surface expression, while the mutant GPIbβ did not. Transient co-expression in 293T cells and stable CHO cell transfection; flow cytometry; DNA sequencing Blood High 10216092
2002 The N-terminal cysteine knot (residues 1–14) of GPIbβ is critical for the conformational interaction with GPIX; N-terminal truncations of GPIbβ missing residues 1–14, 1–26, or 1–31 failed to support GPIX surface expression, and residues 15–32 of GPIbβ are implicated in the key contact with GPIX. N-terminal truncation mutants and GPIbβ/GPIX chimeras expressed in mammalian cells; surface expression by flow cytometry; anti-GPIbβ monoclonal antibody MBC 257.4 developed to map epitope Blood High 12036872
2011 Crystal structures of GPIbβ ectodomain and a GPIbβ/GPIX chimera revealed a quaternary interface between GPIbβ and GPIX, with GPIbβ Tyr106 inserting into a pocket formed by GPIX loops b and c; mutagenesis confirmed this interface, and two BSS mutations A108P and P74R disrupted GPIX surface expression by perturbing this interface. X-ray crystallography of GPIbβ ectodomain and GPIbβ(Eabc) chimera; site-directed mutagenesis; surface expression assays Blood High 21908432
1994 Truncated GPIbα lacking the transmembrane domain and cytoplasmic tail (due to Ser444→stop mutation) is produced, normally glycosylated, and secreted into plasma; residual GPIbβ and GPIX are expressed on the platelet surface without GPIbα, indicating that GPIbβ and GPIX can partially assemble independently of the GPIbα transmembrane/cytoplasmic region. DNA sequencing; neuraminidase digestion; SDS-PAGE; Western blot; flow cytometry of patient platelets Blood Medium 7949089
1998 A Leu40Pro mutation in GPIX causes Bernard-Soulier syndrome with near-normal GPIbα surface levels but severely reduced GPIX and GPV, and GPIbα in this context fails to bind conformation-dependent monoclonal antibodies and cannot support ristocetin-induced agglutination, indicating GPIX is required for proper GPIbα conformation and function. Flow cytometry; GPIX gene sequencing; allele-specific restriction enzyme analysis; ristocetin-induced platelet agglutination; monoclonal antibody binding assays British journal of haematology Medium 9886312
2003 The quinine-dependent antibody binding site on GPIX is localized to the C-terminal extracellular region (amino acids 64–135), with Arg110 and Gln115 being critical residues; mutation of Arg110 to Gln caused the most pronounced reduction in quinine-dependent antibody binding from patient sera. Chimeric mouse/human GPIX constructs expressed in stable CHO cell lines; patient serum binding assays; site-directed mutagenesis Blood High 12738668
2002 A Leu7Pro mutation in the signal peptide hydrophobic core of GPIX abolishes surface expression of the entire GPIb-V-IX complex; co-transfection of GPIXPro7 with normal GPIbα and GPIbβ in CHO cells reproduced the platelet phenotype (no detectable GPIX, low intracellular GPIbα/β, no surface expression), establishing a critical role for the GPIX signal peptide in correct ER insertion and complex biogenesis. DNA sequencing; flow cytometry; Western blot; co-transfection in CHO cells British journal of haematology High 12100158
2001 A Cys8→Arg mutation in mature GPIX disrupts a putative disulfide bond between Cys8 and Cys12, altering secondary structure and causing absence of the GPIb/IX/V complex from the platelet surface in a BSS patient. DNA sequencing; restriction enzyme analysis (BsaAI); flow cytometry; structural inference from disulfide bond disruption British journal of haematology Medium 11167791
2001 Asn45Ser mutation in GPIX causes BSS with decreased disulfide bridge formation between GPIbα and GPIbβ, suggesting GPIX is required not only for correct assembly of the GPIb-IX complex but also for proper disulfide bonding between GPIbα and GPIbβ. Flow cytometry; Western blotting; DNA sequencing; restriction analysis with Fnu4H1 Platelets Medium 11297032 14510954 17804902
2012 GPIX W127X (nonsense) mutation leads to absence of GPIX but residual GPIbα/β heterodimer is still expressed on platelets and CHO-K1 cells; this residual GPIbα/β complex supports adhesion to immobilized von Willebrand factor, type III collagen, and ristocetin-induced agglutination, demonstrating that GPIbα/β can form a functional complex independently of GPIX. Flow cytometry; stable CHO-K1 cell expression; platelet adhesion assay to immobilized VWF and collagen; ristocetin-induced platelet agglutination International journal of hematology Medium 23143686
2023 Lentiviral gene therapy restoring GPIX expression in GP9-knockout megakaryoblastic cell lines and iPSC-derived platelets reverts absence of GPIX on the membrane surface and normalizes platelet size, confirming that GP9/GPIX is necessary and sufficient for correct GPIb-IX-V complex surface localization and normal platelet morphology. CRISPR/gene-editing KO models; lentiviral transduction; flow cytometry; iPSC differentiation to megakaryocytes/platelets; hematopoietic stem cell transduction from BSS patients Molecular therapy. Nucleic acids High 37416759
2021 Cancer cells (A549, MCF-7, MV3) take up intact platelets by dynamin-dependent phagocytosis and subsequently recycle the platelet-specific protein CD42a (GPIX) into their own plasma membrane; this was not observed in non-cancerous 16HBE14o- cells. Confocal laser scanning microscopy; flow cytometry; dynamin inhibitor Dyngo4a; incubation of cancer cells with fluorescently labeled platelets Journal of thrombosis and haemostasis Medium 34592045
2019 A 2460 bp deletion in the canine GP9 gene causing a frameshift and premature stop codon truncating ~two-thirds of the protein abolishes functional GPIb-IX-V complex expression (confirmed by immunocytochemistry) and causes macrothrombocytopenia with platelet adhesion defect resembling human BSS type C, establishing GP9 as the causal gene in Cocker Spaniel BSS. Whole genome sequencing; PCR-based genotyping; immunocytochemistry; pedigree/recessive inheritance analysis PloS one Medium 31484196
2025 Homozygous deletion of GP9 in immortalized megakaryocyte cell lines (imMKCL) reduced proplatelet formation by 96%, and transcriptomic analysis of GP9-/- MKs showed dysregulation of RNA metabolism and actin/tubulin folding pathways, identifying specific molecular pathways dependent on GPIX during megakaryopoiesis. Homozygous GP9 deletion in imMKCL; proplatelet formation assay; RNA-seq at four MK differentiation stages; patient platelet RNA-seq HemaSphere Medium 41017962

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Bernard-Soulier syndrome Kagoshima: Ser 444-->stop mutation of glycoprotein (GP) Ib alpha resulting in circulating truncated GPIb alpha and surface expression of GPIb beta and GPIX. Blood 62 7949089
1999 The critical interaction of glycoprotein (GP) IBbeta with GPIX-a genetic cause of Bernard-Soulier syndrome. Blood 57 10216092
2011 Quaternary organization of GPIb-IX complex and insights into Bernard-Soulier syndrome revealed by the structures of GPIbβ and a GPIbβ/GPIX chimera. Blood 43 21908432
2005 Molecular evolutionary analyses of the odorant-binding protein gene Gp-9 in fire ants and other Solenopsis species. Molecular biology and evolution 41 15987877
2001 High-resolution CryoFESEM of individual cell adhesion molecules (CAMs) in the glycocalyx of human platelets: detection of P-selectin (CD62P), GPI-IX complex (CD42A/CD42B alpha,B beta), and integrin GPIIbIIIa (CD41/CD61) by immunogold labeling and stereo imaging. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 34 11410606
2012 Male reproductive fitness and queen polyandry are linked to variation in the supergene Gp-9 in the fire ant Solenopsis invicta. Proceedings. Biological sciences 33 22535783
2003 Drug-induced thrombocytopenia: localization of the binding site of GPIX-specific quinine-dependent antibodies. Blood 33 12738668
1998 A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV. British journal of haematology 33 9886312
2003 Bernard-Soulier syndrome due to the homozygous Asn-45Ser mutation in GPIX: an unexpected, frequent finding in Germany. British journal of haematology 29 14510954
2004 CYP4AB1, CYP4AB2, and Gp-9 gene overexpression associated with workers of the red imported fire ant, Solenopsis invicta Buren. Gene 27 14960363
2001 Identification of a new mutation in platelet glycoprotein IX (GPIX) in a patient with Bernard-Soulier syndrome. British journal of haematology 27 11167791
2002 A Leu7Pro mutation in the signal peptide of platelet glycoprotein (GP)IX in a case of Bernard-Soulier syndrome abolishes surface expression of the GPIb-V-IX complex. British journal of haematology 26 12100158
2021 Uptake of platelets by cancer cells and recycling of the platelet protein CD42a. Journal of thrombosis and haemostasis : JTH 25 34592045
2009 Current status of a model system: the gene Gp-9 and its association with social organization in fire ants. PloS one 24 19893635
2002 The cysteine knot of platelet glycoprotein Ib beta (GPIb beta) is critical for the interaction of GPIb beta with GPIX. Blood 16 12036872
2014 Expression of foraging and Gp-9 are associated with social organization in the fire ant Solenopsis invicta. Insect molecular biology 15 25315753
2011 Membrane insertion and assembly of epitope-tagged gp9 at the tip of the M13 phage. BMC microbiology 13 21943062
2001 Occurrence of the Asn45Ser mutation in the GPIX gene in a Belgian patient with Bernard Soulier syndrome. Platelets 13 11297032
2016 Generation of induced pluripotent stem cells (iPSCs) from a Bernard-Soulier syndrome patient carrying a W71R mutation in the GPIX gene. Stem cell research 8 27346198
2007 First Turkish case of Bernard-Soulier syndrome associated with GPIX N45S. Acta haematologica 8 17804902
2023 Lentiviral gene therapy reverts GPIX expression and phenotype in Bernard-Soulier syndrome type C. Molecular therapy. Nucleic acids 7 37416759
1996 Flow cytometric platelet enumeration utilizing monoclonal antibody CD42a. Clinical and laboratory haematology 7 9054700
2019 A large deletion in the GP9 gene in Cocker Spaniel dogs with Bernard-Soulier syndrome. PloS one 4 31484196
2012 Platelets with a W127X mutation in GPIX express sufficient residual amounts of GPIbα to support adhesion to von Willebrand factor and collagen. International journal of hematology 4 23143686
2016 Generation of a human induced pluripotent stem cell (iPSC) line from a Bernard-Soulier syndrome patient with the mutation p.Asn45Ser in the GPIX gene. Stem cell research 2 27934591
2024 Dysregulation of platelet serotonin, 14-3-3, and GPIX in sudden infant death syndrome. Scientific reports 1 38750089
2017 Induced pluripotent stem cells derived from Bernard-Soulier Syndrome patient's peripheral blood cells with a p.Phe55Ser mutation in the GPIX gene. Stem cell research 1 28395735
2017 Two novel variants of uncertain significance in GP9 associated with Bernard-Soulier syndrome: Are they true mutations? Platelets 1 29119855
2026 Screening and structure-activity relationship analysis of benzoate repellents against Solenopsis invicta targeting odorant-binding protein GP-9. Pest management science 0 42126138
2025 Transcriptome profiling of megakaryocytes and platelets: Application to GP9- and IKZF5-related thrombocytopenia. HemaSphere 0 41017962
2024 A Novel Variant of GP9 Gene Resulting in Bernard-Soulier Syndrome: A Case Report. Cureus 0 39867007

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