Affinage

GP1BB

Platelet glycoprotein Ib beta chain · UniProt P13224

Length
206 aa
Mass
21.7 kDa
Annotated
2026-06-10
21 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPIbβ is a structural and signaling subunit of the platelet GPIb-IX-V adhesion receptor that couples von Willebrand factor (VWF) binding to cytoskeletal reorganization and intracellular signaling (PMID:41190427, PMID:19694944). Its single leucine-rich-repeat ectodomain forms a quaternary interface with GPIX through insertion of Tyr106 into a pocket built from two GPIX loops, an interaction essential for surface expression of the complex (PMID:21908432), and its extracellular C-terminal cysteine-flanked loop modulates VWF-mediated adhesion under flow (PMID:11816713). GPIbβ is also required for correct GPIbα maturation: disruption of GPIbβ disulfide bonding to GPIbα blocks GPIbα O-glycosylation and ER export and destabilizes GPIX, establishing GPIbβ as a control point for processing and stability of the partner subunits (PMID:12693941). The transmembrane/cytoplasmic boundary of GPIbβ (V144–A161) directly binds the Src-family kinase Lyn to drive bidirectional GPIb-IX signaling, supporting stable platelet adhesion, aggregation, and arterial thrombosis (PMID:41190427), while an intracellular segment (Leu150–Pro170) is required for VWF-induced filopodia formation independent of filamin A, 14-3-3ζ, and Ser166 phosphorylation (PMID:19694944). PKA-dependent phosphorylation of GPIbβ enhances 14-3-3ζ recruitment to the complex (PMID:10627461), and a distinct cytoplasmic motif (residues 177–181, Arg-Leu-X-Ala) binds TRAF4 (PMID:29073066). Conformational change in GPIbβ underlies outside-in activation, as antibodies against GPIbβ can either suppress or potentiate filopodia and GPIb-IX signaling (PMID:33915031), and this signaling drives platelet clearance in vivo (PMID:35305057). The cytoplasmic tail of GPIbβ is dispensable for assembly and trafficking of the receptor, since a frameshift truncating it still permits correct complex assembly at the membrane (PMID:34638529).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 High

    Established that GPIbβ's cytoplasmic domain participates in regulated 14-3-3ζ recruitment to the GPIb-IX complex, linking PKA signaling to the receptor's adaptor binding.

    Evidence GST pulldown with 14-3-3ζ, co-IP in CHO cells and platelets, truncation mutagenesis, forskolin treatment

    PMID:10627461

    Open questions at the time
    • Functional consequence of 14-3-3ζ binding for adhesion or signaling not defined
    • Specific phosphorylated residue not pinpointed in this study
  2. 2001 Medium

    Showed the GPIbβ extracellular domain actively modulates VWF-mediated adhesion rather than serving purely as a structural scaffold.

    Evidence Anti-GPIbβ mAb (RAM.1) epitope mapping, platelet agglutination, and adhesion-under-flow assays of transfected cells

    PMID:11816713

    Open questions at the time
    • Single antibody, single lab
    • Mechanism by which the ectodomain influences GPIbα-VWF binding not structurally resolved
  3. 2003 High

    Defined a dual chaperone-like role for GPIbβ in driving GPIbα glycosylation/maturation and stabilizing GPIX, beyond its adhesion function.

    Evidence Asn64Thr mutant co-expression in CHO cells with metabolic labeling, glycosidase assays, immunoprecipitation, confocal microscopy

    PMID:12693941

    Open questions at the time
    • Based on a single missense mutation in a heterologous system
    • Does not establish whether the maturation defect generalizes to other GPIbβ lesions
  4. 2009 High

    Mapped a discrete GPIbβ intracellular segment (Leu150–Pro170) required for VWF-induced filopodia, distinguishing this signaling output from filamin A, 14-3-3ζ, and Ser166 phosphorylation.

    Evidence Alanine-scanning and deletion mutagenesis in CHO cells with filopodia quantification, confirmed by knock-in mouse model

    PMID:19694944

    Open questions at the time
    • Effector that binds this segment to drive cytoskeletal remodeling not identified
    • Quantitative effect modest (~21-23% reduction)
  5. 2017 High

    Identified TRAF4 as a direct cytoplasmic partner binding a defined GPIbβ Arg-Leu-X-Ala motif, providing a structural basis for a TRAF4-linked signaling branch.

    Evidence X-ray crystallography of TRAF4(290-470)-GPIbβ peptide complex and peptide binding assays

    PMID:29073066

    Open questions at the time
    • Functional/thrombotic consequence of the GPIbβ-TRAF4 interaction not demonstrated in this study
    • Binding shown with peptide, not full-length receptor in platelets
  6. 2011 High

    Solved the GPIbβ ectodomain and GPIbβ/GPIX interface structures, revealing Tyr106 as the key contact required for GPIb-IX surface expression and explaining how some BSS mutations fail despite preserved folding.

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

    PMID:21908432

    Open questions at the time
    • Does not address dynamics of complex assembly in megakaryocytes
    • Stoichiometry of GPIbβ within the full complex not resolved here
  7. 2021 Medium

    Demonstrated that GPIbβ conformational change underlies outside-in GPIb-IX activation, since antibodies to GPIbβ can either suppress or potentiate filopodia and signaling.

    Evidence Reciprocal anti-GPIbβ mAbs (RAM.1 inhibitory, 3G6 potentiating) in platelets and CHO-Ib-IX cells with filopodia and activation readouts

    PMID:33915031

    Open questions at the time
    • Structural nature of the proposed conformational change not visualized
    • Single lab, antibody-based inference
  8. 2021 Medium

    Showed the GPIbβ cytoplasmic domain is dispensable for receptor assembly and trafficking, separating its signaling roles from its structural assembly role.

    Evidence Patient platelets with p.Arg177Serfs*124 frameshift analyzed by flow cytometry, western blot, and family segregation

    PMID:34638529

    Open questions at the time
    • Single family/mutation
    • Does not quantify the signaling deficit caused by tail loss
  9. 2021 Medium

    Established Rab5/PI3P-dependent endocytosis as a regulator of GPIbβ trafficking and proplatelet formation in megakaryocytes.

    Evidence Active/inactive Rab5 mutants (Q79L, N133L) in murine fetal-liver megakaryocytes with fluorescence microscopy, transferrin assay, PI3P inhibition

    PMID:34732055

    Open questions at the time
    • Direct molecular link between Rab5 machinery and GPIbβ not defined
    • Performed in murine megakaryocytes, single lab
  10. 2022 Medium

    Provided causal in vivo evidence that GPIb-IX outside-in signaling through GPIbβ drives platelet clearance.

    Evidence RAM.1 antibody and Fc-devoid derivative in IL4R-IbαTg mice with platelet life-span tracking, plus CHO cell chimera assays

    PMID:35305057

    Open questions at the time
    • Relies on a transgenic constitutively-activated model
    • Downstream clearance effectors not identified
  11. 2025 High

    Identified Lyn as a direct GPIbβ transmembrane/cytoplasmic (V144-A161) partner mediating bidirectional GPIb-IX signaling, and validated this interface as an antithrombotic target.

    Evidence Direct recombinant Lyn-GPIbβ binding with domain mapping, co-IP, inhibitory peptide (mPLβ), biomembrane force probe, and FeCl3 carotid thrombosis mouse model

    PMID:41190427

    Open questions at the time
    • How Lyn binding integrates with the Leu150-Pro170 filopodia segment and TRAF4 branch is unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GPIbβ's distinct cytoplasmic interactions (Lyn, TRAF4, 14-3-3ζ) are coordinated into a unified bidirectional signaling output, and the structural basis of the activating conformational change, remain to be integrated.
  • No structure of the full-length GPIbβ cytoplasmic tail with its partners
  • Hierarchy/timing of Lyn vs TRAF4 vs 14-3-3ζ engagement unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 2 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-109582 Hemostasis 2 R-HSA-162582 Signal Transduction 2
Partners
GP1BAGP9LYNTRAF4YWHAZ
Complex memberships
GPIb-IX-V complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 The cytoplasmic domain of GPIbβ regulates 14-3-3ζ binding to the GPIb/IX/V complex. PKA-dependent phosphorylation of GPIbβ (induced by forskolin) enhances GPIbβ binding to 14-3-3ζ and increases 14-3-3ζ co-immunoprecipitation with GPIbα. Truncations of GPIbα that eliminate GPIbα binding to 14-3-3ζ also eliminate GPIbβ binding, indicating coordinated regulation. GST pulldown with 14-3-3ζ fusion protein, co-immunoprecipitation in CHO cells and platelets, truncation/deletion mutagenesis of GPIbα and GPIbβ, forskolin treatment Blood High 10627461
2011 Crystal structure of the GPIbβ ectodomain reveals a single leucine-rich repeat with N- and C-terminal disulfide-bonded capping regions. A chimeric GPIbβ/GPIX structure identified a quaternary interface where GPIbβ Tyr106 inserts into a pocket formed by two GPIX loops (b,c). Mutagenesis confirmed this interface is essential for GPIb-IX complex surface expression; BSS mutations A108P and P74R maintain GPIbβ folding/secretion but abolish GPIX surface expression. X-ray crystallography of GPIbβ ectodomain and GPIbβ/GPIX chimera, site-directed mutagenesis, flow cytometry of surface expression Blood High 21908432
2001 The extracellular domain of GPIbβ modulates vWF-mediated platelet adhesion. An anti-GPIbβ monoclonal antibody (RAM.1) mapped to the COOH-terminal leucine-rich flanking cysteine loop inhibited ristocetin-induced platelet agglutination, botrocetin-induced vWF binding, and adhesion of GPIb/V/IX-transfected cells to vWF under flow, increasing rolling velocity and decreasing resistance to detachment. Monoclonal antibody epitope mapping with synthetic peptides, western blot, co-immunoprecipitation, platelet aggregation assays, cell adhesion under flow Thrombosis and haemostasis Medium 11816713
2003 A single missense mutation (Asn64→Thr) in the extracellular domain of GPIbβ prevents disulfide bonding of GPIbβ to GPIbα, blocks O-glycosylation and maturation of GPIbα (retaining it in the ER as ~66 kDa rather than 130 kDa), and destabilizes GPIX, demonstrating that GPIbβ has a dual role in controlling processing/maturation of GPIbα and stability of GPIX. DNA sequencing, co-expression in CHO cells, flow cytometry, confocal microscopy, immunoprecipitation, 35S metabolic labeling, glycosidase assays Biochemistry High 12693941
2009 The intracellular domain of GPIbβ (specifically residues Leu150–Pro170, with key residues Arg164, Leu165, Leu167, Thr168, and Pro170) is required for efficient filopodia formation upon VWF adhesion, independent of filamin A or 14-3-3ζ binding sites and independent of Ser166 PKA phosphorylation. Deletion of juxtamembrane or central segments reduced filopodia-forming cells by ~21–23%. Knock-in mice with GPIbβ intracellular deletion confirmed impaired filopodia upon VWF adhesion. CHO cell expression of GPIbβ deletion/point mutants, filopodia quantification on VWF matrix, alanine scanning mutagenesis, knock-in mouse model Journal of thrombosis and haemostasis High 19694944
2017 Crystal structure of TRAF4 (residues 290–470) in complex with a GPIbβ peptide (residues 177–181) shows GPIbβ binds a unique shallow surface composed of two hydrophobic pockets on TRAF4. The TRAF4-binding motif Arg-Leu-X-Ala was identified in GPIbβ and also present in GPVI and TGF-β receptor. X-ray crystallography of TRAF4–GPIbβ peptide complex, peptide binding assay Proceedings of the National Academy of Sciences of the United States of America High 29073066
2021 Anti-GPIbβ antibody RAM.1 inhibits GPIb-IX-associated filopodia formation and nearly all GPIb-IX-related signaling, while a novel anti-GPIbβ antibody 3G6 potentiates filopodia formation and GPIb-IX activation. These divergent modulatory effects of two antibodies both targeting GPIbβ indicate that conformational changes in GPIbβ underlie outside-in activation via GPIb-IX. Monoclonal antibody functional assays in platelets and CHO-Ib-IX cells, flow cytometry, filopodia quantification, affinity binding to purified GPIbβ and GPIb-IX Journal of thrombosis and haemostasis Medium 33915031
2021 A frameshift mutation affecting only the cytoplasmic domain of GPIbβ (p.Arg177Serfs*124) causes mild BSS with moderate reduction of GPIb-IX complex surface expression, but all mutant GPIbβ present in platelets is correctly assembled into the GPIb-IX complex at the plasma membrane, demonstrating that the cytoplasmic domain of GPIbβ is not required for assembly and trafficking of the GPIb-IX receptor. Flow cytometry, western blot, DNA sequencing, family segregation analysis International journal of molecular sciences Medium 34638529
2021 Rab5-dependent endocytosis regulates GPIbβ trafficking in megakaryocytes. Active Rab5 (Q79L) causes GPIbβ accumulation in enlarged early endosomes (phosphatidylinositol 3-monophosphate-dependent), while inactive Rab5 (N133L) causes GPIbβ plasma membrane retention. Rab5 activity modulates proplatelet formation. GFP-Rab5 wild-type and point mutant (Q79L, N133L) expression in primary murine fetal liver-derived megakaryocytes, fluorescence microscopy, transferrin internalization assay, PI3P inhibition Arteriosclerosis, thrombosis, and vascular biology Medium 34732055
2022 The anti-GPIbβ antibody RAM.1 (and a Fc-devoid derivative) abolishes constitutive filopodia and significantly extends platelet life span in IL4R-IbαTg mice (which have constitutively exposed GPIbα Trigger sequence), providing causal evidence that GPIb-IX outside-in signaling through GPIbβ drives platelet clearance. Confocal microscopy of CHO cells expressing chimeric IL4R-Ibα complex, flow cytometry, endogenous platelet life span tracking with labeled anti-GPIX antibody in transgenic mice Journal of thrombosis and haemostasis Medium 35305057
2025 Src family kinase Lyn directly binds to GPIbβ at the transmembrane/cytoplasmic domain interface (residues V144–A161). This interaction is required for both inward GPIb-IX ligand-induced intracellular signaling and outbound signals that enhance VWF-GPIb-IX interaction. An inhibitory peptide (mPLβ) targeting this site blocked GPIbβ-Lyn interaction, Lyn/SFK activation, stable platelet adhesion and aggregation, and in vivo arterial thrombosis in mice. Direct binding assay of recombinant Lyn to GPIbβ fragments, co-immunoprecipitation, inhibitory peptide (mPLβ) in platelets and CHO cells, biomembrane force probe for VWF-GPIb molecular bonding, FeCl3-induced carotid artery thrombosis mouse model, nanoparticle peptide delivery Circulation research High 41190427

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Cytoplasmic domains of GpIbalpha and GpIbbeta regulate 14-3-3zeta binding to GpIb/IX/V. Blood 50 10627461
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
2001 A novel monoclonal antibody against the extracellular domain of GPIbbeta modulates vWF mediated platelet adhesion. Thrombosis and haemostasis 43 11816713
2016 Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia. Blood 39 28064200
2011 Deletion of human GP1BB and SEPT5 is associated with Bernard-Soulier syndrome, platelet secretion defect, polymicrogyria, and developmental delay. Thrombosis and haemostasis 33 21800012
2003 A novel missense mutation shows that GPIbbeta has a dual role in controlling the processing and stability of the platelet GPIb-IX adhesion receptor. Biochemistry 24 12693941
2013 Bernard-Soulier syndrome caused by a hemizygous GPIbβ mutation and 22q11.2 deletion. Pediatrics international : official journal of the Japan Pediatric Society 22 23566026
2017 Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression. Scientific reports 16 28821815
2017 Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI. Proceedings of the National Academy of Sciences of the United States of America 13 29073066
2021 Differential regulation of the platelet GPIb-IX complex by anti-GPIbβ antibodies. Journal of thrombosis and haemostasis : JTH 12 33915031
2009 The platelet glycoprotein GPIbbeta intracellular domain participates in von Willebrand factor induced-filopodia formation independently of the Ser 166 phosphorylation site. Journal of thrombosis and haemostasis : JTH 10 19694944
2008 Bernard-Soulier syndrome: novel nonsense mutation in GPIbbeta gene affecting GPIb-IX complex expression. Annals of hematology 10 18825380
2021 A Novel Mutation in GP1BB Reveals the Role of the Cytoplasmic Domain of GPIbβ in the Pathophysiology of Bernard-Soulier Syndrome and GPIb-IX Complex Assembly. International journal of molecular sciences 6 34638529
2009 The same genetic defect in three Tunisian families with Bernard Soulier syndrome: a probable founder Stop mutation in GPIbβ. Annals of hematology 5 19484238
2024 Bernard-Soulier syndrome caused by a novel GP1BB variant and 22q11.2 deletion. International journal of hematology 4 38625506
2021 Early Endosomal GTPase Rab5 (Ras-Related Protein in Brain 5) Regulates GPIbβ (Glycoprotein Ib Subunit β) Trafficking and Platelet Production In Vitro. Arteriosclerosis, thrombosis, and vascular biology 4 34732055
2022 Fast clearance of platelets in a commonly used mouse model for GPIbα is impeded by an anti-GPIbβ antibody derivative. Journal of thrombosis and haemostasis : JTH 3 35305057
2021 A novel frameshift GP1BB mutation causes autosomal dominant macrothrombocytopenia with decreased vWF receptor expression but normal platelet aggregation. Platelets 3 33813986
2026 Bernard-Soulier Syndrome: Identification of a Novel GP1BB Variant in a Mauritanian Patient. Molecular genetics & genomic medicine 1 41566116
2021 A homozygous loss-of-function mutation in GP1BB causing variable clinical phenotypes in a family with Bernard-Soulier syndrome. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 1 33657022
2025 Direct Binding of Lyn to GPIbβ Transmits 2-Way GPIb-IX Signaling to Stimulate Platelet Activation and VWF Binding. Circulation research 0 41190427

Missed literature

Know a paper Affinage missed for GP1BB? Flag it for the maintainers and the community.

No submissions yet.