Affinage

GP1BA

Platelet glycoprotein Ib alpha chain · UniProt P07359

Length
652 aa
Mass
71.5 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPIbα is the ligand-binding subunit of the platelet GPIb-IX-V complex that initiates hemostasis and thrombosis by capturing von Willebrand factor (VWF) and recruiting thrombin to the platelet surface (PMID:17075060, PMID:24316004). Its extracellular domain engages thrombin exclusively at anion-binding exosite II through residues D274–E285, leaving exosite I free for PAR-1 recognition (PMID:24316004, PMID:19591434), and the same complex can simultaneously bridge two thrombin molecules to scaffold adhesion (PMID:12855811). Binding to VWF is governed by force-dependent catch-to-slip bond behavior coupled to A1-domain conformational unfolding, with A1 stability allosterically tuning the force threshold for engagement—a mechanism that disease-associated VWF and GPIbα mutations shift toward higher or lower affinity (PMID:20713003, PMID:19619477, PMID:12637314). Engagement of GPIbα is essential and VWF-independent for platelet recruitment to subendothelium and growing thrombi under arterial flow (PMID:17075060). Beyond adhesion, GPIbα is a signaling receptor: its intracellular tail binds 14-3-3ζ and PI3K to drive filopodia formation, αIIbβ3 activation, and platelet spreading, with these signals cooperating with GPVI, PAR4, and CLEC-2 downstream pathways including FAK/NOX1-dependent ROS generation (PMID:10627461, PMID:34134470, PMID:26569550, PMID:35157766). The GPIbα cytoplasmic tail also anchors the membrane skeleton via filamin A, a coordinated interaction required for mechanical stability under shear, megakaryocyte demarcation membrane system formation, directional platelet release, and normal platelet size (PMID:21156842, PMID:22174152, PMID:11937271, PMID:37922495); loss of GPIbα or its filamin link produces macrothrombocytopenia. GPIbα surface levels are controlled by ADAM17-mediated ectodomain shedding from an intracellular GPIbα subpopulation, a process restrained by PKA and triggered by desialylation, ROS, and mitochondrial permeability transition, and shedding is a causal driver of storage- and refrigeration-induced platelet clearance (PMID:15345652, PMID:22101895, PMID:37001816, PMID:19181367, PMID:23909816, PMID:27417583). GPIbα additionally serves as the receptor for S100A8/A9 to generate procoagulant platelets (PMID:36026606), engages leukocyte Mac-1 to promote thrombosis and modulate monocyte transcription (PMID:28555620), can be transferred to monocytes via extracellular vesicles to enable VWF-dependent leukocyte recruitment (PMID:31467123), and is required for platelet-mediated hepatic thrombopoietin generation through a direct hepatocyte interaction of its N-terminal domain (PMID:29794068). Loss-of-function in GPIbα underlies Bernard-Soulier syndrome, manifesting as reduced circulating TPO and macrothrombocytopenia (PMID:29794068).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1992 High

    Establishing that the HPA-2 alloantigen system maps to a Thr145Met polymorphism on GPIbα localized the immunologically and clinically relevant epitope to the VWF-binding region.

    Evidence DNA sequencing, RFLP, and agglutination inhibition assay across donors

    PMID:1346615

    Open questions at the time
    • Did not establish the functional consequence of the dimorphism for ligand binding
    • No structural localization within the N-terminal domain
  2. 2000 High

    Two studies defined the GPIbα cytoplasmic tail as a docking platform, showing residues 570–590 bind 14-3-3ζ under PKA regulation, answering how an adhesion receptor couples to intracellular signaling.

    Evidence Truncation mutagenesis, GST-pulldown, and co-IP in CHO cells and platelets; LRR-region glycosylation/expression analysis in CHO cells

    PMID:10627461 PMID:10928479

    Open questions at the time
    • Downstream signaling consequences of 14-3-3ζ binding not resolved
    • Did not define how shear-induced dissociation is sensed
  3. 2002 High

    Demonstrating that GPIbα-null megakaryocytes have defective demarcation membrane systems established a developmental role for GPIbα in platelet biogenesis beyond hemostasis.

    Evidence Electron microscopy and immunogold quantification in GPIbα-null and human GPIbα transgenic rescue mice

    PMID:11937271

    Open questions at the time
    • Did not identify the molecular effector linking GPIbα to membrane development
    • Mechanistic link to filamin not yet established at this stage
  4. 2003 High

    Structural and single-molecule work defined how GPIbα engages thrombin and how a gain-of-function mutation tunes the VWF tether bond, clarifying both the thrombin-recruitment scaffold and the kinetic basis of shear-dependent adhesion.

    Evidence X-ray crystallography of GPIbα–thrombin; single-molecule tether-bond kinetics of PT-VWD platelets; PAR-desensitized platelet signaling with blocking antibody and Mocarhagin

    PMID:12637314 PMID:12719784 PMID:12775575 PMID:12855811

    Open questions at the time
    • Crystallographic dual-thrombin stoichiometry later refined to exosite-II-only binding
    • PAR-independent aggregation pathway defined only pharmacologically without genetic confirmation
  5. 2004 High

    Identifying ADAM17 as the metalloproteinase that sheds the GPIbα ectodomain established the enzymatic basis for surface receptor downregulation and platelet clearance.

    Evidence TACE-inactive chimeric mice, TACE inhibitors, and in vivo/in vitro shedding assays

    PMID:15345652

    Open questions at the time
    • Did not define the physiological trigger or subcellular site of shedding
    • Upstream regulation of ADAM17 unresolved
  6. 2006 High

    Replacing the GPIbα ectodomain in vivo showed it is absolutely and VWF-independently required for platelet recruitment under arterial flow, establishing GPIbα as the indispensable adhesion initiator; a tail-derived peptide implicated cytoplasmic residues 557–569 in adhesion signaling.

    Evidence IL4Rα/GPIbα transgenic mice with intravital microscopy and adoptive transfer; cell-penetrating GPIbα(557–569) peptide in platelet and CHO adhesion assays

    PMID:17075060 PMID:17100656

    Open questions at the time
    • Peptide approach lacked genetic confirmation
    • Nature of the VWF-independent adhesion ligand not defined
  7. 2009 High

    Biophysical mapping placed the thrombin interface at GPIbα residues D274–E285 on exosite II and showed PKA inhibition drives metalloproteinase-dependent shedding, beginning to delineate both the thrombin-binding chemistry and shedding regulation.

    Evidence NMR/AUC/HDX-MS of the thrombin interface; AFM and unfolding thermodynamics of VWD A1 mutants; PKA inhibitor/forskolin shedding assays

    PMID:19181367 PMID:19591434 PMID:19619477

    Open questions at the time
    • PKA-shedding link defined pharmacologically without genetic confirmation
    • Mechanism connecting PKA to ADAM17 activity unresolved
  8. 2010 High

    A cluster of studies established the GPIbα–filamin A interaction as the membrane-skeleton anchor required for shear resistance, and defined the catch-slip thermodynamics and VWF self-association that govern force-dependent adhesion and mechanotransduction.

    Evidence Filamin-binding-defective hGPIbα(FW) transgenic mice under high shear; CD/thermodynamic A1 binding analysis; GPIbα-selective COS-7 agonist with kinase inhibitors; shear VWF self-association binding assays

    PMID:20367574 PMID:20696943 PMID:20713003 PMID:21156842

    Open questions at the time
    • Syk dependence of GPIbα signaling later contested
    • Self-association model inferred from binding without structural validation
  9. 2011 High

    Linking GPIbα expression to filamin A trafficking and platelet size, and showing desialylation routes GPIbα to ADAM17 shedding and clearance, connected receptor biogenesis and turnover to platelet homeostasis.

    Evidence ESC-derived platelets and HEK293T trafficking assays; sialidase inhibitors with Adam17-null platelets and in vivo clearance assays

    PMID:22101895 PMID:22174152

    Open questions at the time
    • Trafficking mechanism coordinating GPIbα and filamin not molecularly resolved
    • How desialylation exposes the cleavage site unclear
  10. 2013 High

    Refining the thrombin interface to exosite-II-only binding and identifying MPTP-driven mitochondrial ROS as a shedding trigger sharpened both the thrombin-recruitment model and the upstream control of GPIbα cleavage.

    Evidence Mutagenesis, crystallography, and NMR of thrombin binding; MPTP/MCU pharmacology and mitochondrial ROS measurements for shedding

    PMID:23909816 PMID:24316004

    Open questions at the time
    • MPTP-shedding pathway defined pharmacologically without genetic confirmation of individual steps
    • Physiological context triggering MPTP-dependent shedding unclear
  11. 2015 Medium

    Demonstrating that GPIbα cooperates with PAR4 via FAK and NOX1 to generate thrombin-induced ROS placed GPIbα within a redox signaling node downstream of platelet activation.

    Evidence GPIbα-cleaving protease, PAR antagonists, PAR4-deficient mice, and flow cytometric ROS assays

    PMID:26569550

    Open questions at the time
    • Direct physical coupling between GPIbα and the FAK/NOX1 module not shown
    • Pharmacological dissection without GPIbα genetic confirmation
  12. 2017 High

    Two studies extended GPIbα biology to leukocyte engagement via Mac-1 and resolved the contested role of Syk, showing Syk activity is dispensable for VWF/GPIbα-induced platelet responses.

    Evidence Mac-1 knockout and binding-site mutant mice with adoptive transfer and injury models; selective Syk inhibitors comparing GPIbα versus GPVI signaling

    PMID:28555620 PMID:28598382

    Open questions at the time
    • Syk negative result derived from a single pharmacological study
    • Molecular consequences of Mac-1–GPIbα binding for monocyte Foxp1 not fully resolved
  13. 2018 High

    Establishing that the GPIbα N-terminal domain is required for platelet-driven hepatic thrombopoietin generation revealed a homeostatic feedback role linking platelet receptor to TPO production.

    Evidence GPIbα-null and IL4R/GPIbα transgenic mice, BSS patient samples, transfusion rescue, and hepatocyte co-culture with GPIbα-coupled beads

    PMID:29794068

    Open questions at the time
    • Hepatocyte receptor/partner for GPIbα not identified
    • Signaling pathway driving hepatic TPO transcription unresolved
  14. 2019 Medium

    Discovery that GPIbα can be transferred to monocytes via extracellular vesicles, and that a soluble T-cell-derived GPIbα acts through Mac-1, expanded GPIbα function into thrombo-inflammatory leukocyte recruitment and cytokine signaling.

    Evidence Flow cytometry, intravital and in vitro rolling assays with anti-GPIbα blockade; MS identification, recombinant GPIbα, antibody blockade, and Mac-1 KO mice

    PMID:31467123 PMID:31594856

    Open questions at the time
    • T-cell as a source of soluble GPIbα warrants independent replication
    • Receptor mechanism on hepatocytes/leukocytes incompletely defined
  15. 2022 High

    A set of studies established CLEC-2 as a downstream effector of GPIbα-driven integrin activation, identified GPIbα as the S100A8/A9 receptor for procoagulant platelet formation, and dissected how VWF A1 linkers allosterically tune GPIbα affinity.

    Evidence Platelet-specific CLEC-2 KO mice with TTP model; GPIbα ectodomain blockade, BSS platelets, and GPIbα-deficient mice; HDX and thermodynamic analysis of A1 linker constructs

    PMID:35157766 PMID:35532124 PMID:36026606

    Open questions at the time
    • Physical coupling between GPIbα and CLEC-2 not defined
    • Mechanism translating S100A8/A9 binding into phosphatidylserine exposure unresolved
  16. 2023 High

    Demonstrating that ADAM17 and a GPIbα substrate subpopulation are stored intracellularly redefined shedding as a spatially controlled event requiring strong stimulation rather than constitutive surface cleavage.

    Evidence Immunogold transmission EM, immunoprecipitation, quantitative western blotting, and membrane-permeable versus proteinaceous ADAM17 inhibitors

    PMID:37001816

    Open questions at the time
    • Trafficking route exposing the intracellular GPIbα subpopulation unclear
    • The non-hemostatic function implied by slow shedding kinetics not defined
  17. 2024 High

    Showing the GPIbα–filamin A interaction directs demarcation membrane formation and the directional release of platelet buds into sinusoids linked the membrane-skeleton anchor to spatially controlled thrombopoiesis.

    Evidence Filamin-binding-defective hGPIbα(FW) transgenic mice with electron microscopy and intravital megakaryocyte imaging

    PMID:37922495

    Open questions at the time
    • Molecular cue establishing release directionality not identified
    • How filamin redistribution is regulated by the GPIbα link unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the hepatocyte receptor mediating GPIbα-dependent thrombopoietin generation and the molecular pathway coupling GPIbα adhesion signaling to its multiple cooperating receptors (CLEC-2, PAR4, FAK/NOX1) remain to be defined.
  • No identified hepatocyte partner for GPIbα N-terminal domain
  • Physical basis of GPIbα–CLEC-2 functional coupling unknown
  • Mechanism integrating GPIbα signaling with redox and procoagulant outputs incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0098631 cell adhesion mediator activity 3 GO:0001618 virus receptor activity 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-109582 Hemostasis 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
14-3-3ΖCLEC-2FILAMIN AMAC-1PI3KS100A8/A9THROMBINVWF
Complex memberships
GPIb-IX-V complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Crystal structure of the GPIbα–thrombin complex at 2.6 Å resolution reveals that GPIbα simultaneously contacts exosite I of one thrombin molecule and exosite II of a second thrombin molecule, providing a scaffold that could drive tight platelet adhesion. X-ray crystallography (2.6 Å resolution) Science High 12855811
2013 GPIbα binds exclusively to thrombin's anion-binding exosite II (not exosite I), serving to recruit thrombin to the platelet surface while leaving exosite I free for PAR-1 recognition; demonstrated by mutational analysis, binding studies, X-ray crystallography, and NMR. Mutational analysis, binding studies, X-ray crystallography, NMR spectroscopy Journal of Molecular Biology High 24316004
2009 NMR, AUC, and hydrogen-deuterium exchange studies show that GPIbα residues D274–E285 interact with thrombin's anion-binding exosite II in an extended conformation with 1:1 stoichiometry, and binding causes long-range conformational effects on thrombin. 1D/2D NMR, analytical ultracentrifugation, hydrogen-deuterium exchange coupled with MALDI-TOF MS Biochemistry High 19591434
2004 ADAM17 (TACE) is the key metalloproteinase mediating ectodomain shedding of GPIbα in platelets; TACE-deficient chimeric mice show ~90% reduction in soluble glycocalicin in plasma, increased surface GPIbα, and improved post-transfusion recovery and hemostatic function of damaged platelets. Chimeric mouse model with inactive TACE (TACEΔZn/ΔZn), TACE inhibitors (TAP1, TMI-1), in vivo and in vitro shedding assays Circulation Research High 15345652
2006 GPIbα is absolutely required for platelet recruitment to exposed subendothelium and to growing thrombi under arterial flow conditions, independent of VWF binding; transgenic mice expressing GPIbα with the extracellular domain replaced by IL-4Rα showed virtually absent platelet adhesion and completely inhibited arterial thrombus formation. Transgenic mouse model (IL4Rα/GPIbα-tg), intravital microscopy of mesenteric arterioles, adoptive transfer experiments Proceedings of the National Academy of Sciences High 17075060
2000 The cytoplasmic domain of GPIbα (residues 570–590) is required for binding 14-3-3ζ; deletion of Trp570–Ser590 eliminates 14-3-3ζ binding. PKA-dependent phosphorylation of GPIbβ enhances 14-3-3ζ binding to the GPIb/IX/V complex. Under shear stress-induced platelet aggregation, 14-3-3ζ dissociates from GPIbα. Truncation/deletion mutagenesis, GST-pulldown, co-immunoprecipitation in CHO cells and human platelets, shear stress assay Blood High 10627461
2010 The GPIbα–filamin A interaction is essential for maintaining membrane skeletal stability under high shear stress; disrupting this interaction (Phe568Ala/Trp570Ala mutations in human GPIbα) leads to unstable membrane tethers, defective platelet adhesion, and membrane disintegration at pathological shear rates (5,000–40,000 s⁻¹), without altering intrinsic ligand-binding function or integrin αIIbβ3-dependent spreading. Transgenic mouse model expressing filamin-binding-defective hGPIbα(FW), high-shear flow assays, intravital microscopy Blood High 21156842
2011 GPIbα regulates platelet size by controlling the subcellular localization of filamin A; coordinated expression of GPIbα and filamin is required for efficient trafficking of either protein to the cell surface, and their ratio determines normal proplatelet/platelet size. Embryonic stem cell differentiation into platelets, filamin knockdown, GPIbα overexpression, HEK293T trafficking assays Blood High 22174152
2011 Desialylation of GPIbα by platelet sialidases (Neu1, Neu3) after refrigeration targets it for ADAM17-mediated ectodomain shedding; desialylation alone (without metalloproteinase-mediated shedding) is sufficient to cause rapid clearance of platelets from circulation. Sialidase inhibitor studies, Adam17ΔZn/ΔZn mouse platelets, metalloproteinase inhibitor GM6001, in vivo platelet clearance assays Blood High 22101895
2017 Leukocyte integrin Mac-1 engages platelet GPIbα to promote thrombosis; Mac-1-deficient mice and mice with a Mac-1 mutation at the GPIbα-binding site show delayed thrombosis, and adoptive transfer of wild-type leukocytes rescues the defect. Mac-1:GPIbα interaction regulates the transcription factor Foxp1 in monocytes/macrophages. Mac-1 knockout mice, Mac-1 binding-site mutant mice, adoptive leukocyte transfer, carotid artery and cremaster microvascular injury models, small-molecule targeting Nature Communications High 28555620
2018 GPIbα is required for platelet-mediated hepatic thrombopoietin (TPO) generation; GPIbα-null mice and Bernard-Soulier syndrome patients have reduced circulating TPO due to decreased hepatic TPO mRNA transcription. The N-terminal extracellular domain of GPIbα is specifically required, and this function is independent of platelet desialylation. In vitro hepatocyte co-culture with GPIbα-coupled beads confirms direct GPIbα-dependent hepatocyte signaling. GPIbα-/- mouse model, BSS patient samples, platelet transfusion rescue experiments, hepatocyte co-culture with GPIbα-coupled beads, IL4R/GPIbα-transgenic mice, blocking antibodies Blood High 29794068
2002 GPIbα is essential for membrane development in maturing megakaryocytes; its absence leads to poorly developed demarcation membrane system, reduced internal membrane pool, abnormal proplatelet production, and ultimately macrothrombocytopenia. Rescue with human GPIbα transgene corrects all ultrastructural defects. Electron microscopy, immunogold labeling, computer-based membrane quantification in GPIbα-null and GPIbα-null/hTg rescue mice Experimental Hematology High 11937271
2024 The GPIbα–filamin A interaction is required for demarcation membrane system (DMS) formation, correct subcellular distribution of filamin within megakaryocytes, and directional release of platelet buds into sinusoids; disrupting this interaction causes misdirected bud release into bone marrow interstitium and macrothrombocytopenia. Transgenic mouse model expressing filamin-binding-defective hGPIbα(FW), electron microscopy, intravital imaging of megakaryocytes Blood High 37922495
2022 The last 24 residues of the GPIbα intracellular tail (harboring 14-3-3 and PI3K binding sites) are required for VWF-dependent signaling (filopodia formation) and GPVI-mediated signaling (P-selectin exposure, αIIbβ3 activation, pSyk); deletion of this domain reduces platelet spreading on CRP and reduces platelet aggregate formation on collagen under shear, without affecting ligand binding or ADP/thrombin responses. CRISPR-Cas9 GPIbαΔsig/Δsig transgenic mouse, flow assays, immunoblotting (pSyk), platelet spreading and aggregation assays Haematologica High 34134470
2003 Thrombin binding to GPIbα (blocked by anti-GPIbα antibody VM16d or GPIbα cleavage by Mocarhagin) induces platelet aggregation via a signaling cascade independent of PAR-1 and PAR-4; this cascade activates Rho kinase p160ROCK (shape change), causes MEK-1 phosphorylation, and promotes fibrin binding to resting αIIbβ3, leading to fibrin-dependent platelet aggregation and clot retraction. PAR-desensitized platelets, function-blocking antibody, GPIbα-cleaving protease (Mocarhagin), signaling inhibitors, aggregometry Thrombosis and Haemostasis Medium 12719784
2010 GPIbα-selective activation (by multivalent VWF-A1/R543W-expressing COS-7 cells) triggers platelet aggregation through a signaling pathway dependent on Src, PI3K, and Syk, producing tyrosine phosphorylation patterns comparable to GPVI/collagen stimulation, establishing GPIbα as both an adhesion and signaling receptor. GPIbα-selective COS-7 cell agonist, kinase inhibitors, aggregometry, phosphorylation analysis with anti-Syk antibodies Platelets Medium 20367574
2017 Syk kinase activity is dispensable for VWF/GP1b-induced platelet adhesion, agglutination, aggregation, and secretion; selective Syk inhibitors (OXSI-2, PRT-060318) block GPVI- but not GP1b-mediated platelet activation and signaling. Selective Syk inhibitors, VWF-induced aggregation/adhesion assays, comparison with GPVI agonist CRP in human and mouse platelets International Journal of Molecular Sciences Medium 28598382
2015 GPIbα and PAR4 cooperate to generate thrombin-induced reactive oxygen species (ROS) in platelets via focal adhesion kinase (FAK) and NADPH oxidase 1 (NOX1); removal of the GPIbα ligand-binding region completely inhibits thrombin-induced ROS, and PAR4 deficiency abolishes it in mice. GPIbα-cleaving Naja kaouthia protease, PAR1/PAR4 antagonists, PAR4-deficient mice, flow cytometry ROS assay Redox Biology Medium 26569550
2010 VWF self-associates on platelet GPIbα under hydrodynamic shear (>60–70 dyne/cm²), increasing effective VWF size and enhancing mechanotransduction and platelet activation through increased drag force on the receptor. Fluorescence-labeled VWF binding assays under shear, recombinant VWF lacking A1-domain (ΔA1-488), shear stress apparatus, whole blood flow assays Blood Medium 20696943
2010 The thermodynamic mechanism of VWF A1–GPIbα binding involves catch-to-slip bond behavior coupled to A1 domain conformational unfolding; A1 binds GPIbα with ~20-fold higher affinity in an intermediate (partially unfolded) conformation, and force-induced dissociation shifts equilibrium toward this high-affinity state. Circular dichroism, thermodynamic binding analysis, allosteric binding model, reduction/carboxyamidation of A1 disulfide Biophysical Journal Medium 20713003
2009 Type 2B VWD mutations (R1306Q, I1309V) destabilize the A1 domain structure and lower the force threshold for catch-to-slip bond transition with GPIbα, while a type 2M mutation (G1324S) stabilizes A1 and raises this threshold; A1 conformational stability is allosterically coupled to force-dependent GPIbα binding kinetics. Protein unfolding thermodynamics, atomic force microscopy (single-bond dissociation kinetics), site-specific VWF mutations Biophysical Journal High 19619477
1999 GPIbα interacts with the FcγRIIA receptor via residues R542G543R544 on GPIbα and D298D299D300 on FcγRIIA, suggesting that GPIb-IX-V signaling leading to platelet activation may be partially mediated through FcγRIIA. Yeast two-hybrid system, mutagenesis Biochemical and Biophysical Research Communications Low 10581159
2022 S100A8/A9 (calprotectin) induces formation of procoagulant (phosphatidylserine-positive) platelets by binding GPIbα; this was demonstrated using recombinant GPIbα ectodomain blockade, Bernard-Soulier syndrome platelets (GPIb-IX-V deficient), and mice lacking the extracellular domain of GPIbα, with a supporting role for CD36. Recombinant GPIbα ectodomain blockade, BSS patient platelets, GPIbα extracellular domain-deficient mice, flow cytometry, perfusion assays Blood High 36026606
2019 Platelet-derived extracellular vesicles transfer GPIbα to blood monocytes via P-selectin-dependent adhesion stabilized by phosphatidylserine binding; GPIbα-positive monocytes then tether and roll on immobilized VWF or adhere to TGF-β1-treated endothelium in a GPIbα-dependent manner, providing an alternative thrombo-inflammatory leukocyte recruitment pathway. Flow cytometry, intravital microscopy (cremaster, carotid), in vitro rolling assays, function-blocking anti-GPIbα antibody, mouse in vivo models Haematologica High 31467123
2019 GPIbα-derived soluble protein produced by T cells acts through Mac-1 integrin on monocytes to stimulate PGE2, IL-1β, and IL-6 production in MDP-activated monocytes; anti-GPIbα or anti-Mac-1 antibody blockade inhibits this cytokine production, and recombinant GPIbα protein increases PGE2 production. Mass spectrometry identification, antibody blockade, recombinant GPIbα addition, Mac-1 KO mice in vivo, conditioned medium experiments Science Signaling Medium 31594856
2016 Specific inhibition of GPIbα shedding (using monoclonal antibody 5G6 Fab) during platelet storage preserves GPIbα surface levels and significantly improves post-transfusion platelet recovery and hemostatic function without altering platelet activation, degranulation, or aggregation, demonstrating that GPIbα shedding is a causal mechanism of storage-induced platelet clearance. Monoclonal antibody Fab fragment (5G6) specific for GPIbα shedding inhibition, room-temperature platelet storage, transfusion into mice, ex vivo thrombus formation under shear flow Arteriosclerosis, Thrombosis, and Vascular Biology High 27417583
2023 ADAM17 and its GPIbα substrate are both stored intracellularly in platelets, not on the surface; ADAM17 localizes to a distinct intracellular membrane system separate from α- and dense granules. Only a GPIbα subpopulation that becomes accessible after strong stimulation serves as ADAM17 substrate, and shedding occurs with kinetics (20 min–3 h) suggesting a role beyond hemostasis. Membrane-permeable ADAM17 inhibitors (but not proteinaceous inhibitors) can block shedding. Transmission electron microscopy with immunogold staining, immunoprecipitation, quantitative western blotting, selective inhibitors Journal of Thrombosis and Haemostasis High 37001816
2022 CLEC-2 deletion in platelets inhibits αIIbβ3 activation induced by VWF binding to GPIbα without preventing VWF binding itself, demonstrating that CLEC-2 acts downstream of GPIbα to mediate integrin activation and platelet aggregation in TTP-like conditions. Platelet-specific CLEC-2 knockout mice, VWF-binding assays, αIIbβ3 activation assays, mouse TTP model (anti-ADAMTS13 antibody + VWF infusion) Blood High 35157766
2006 A cell-penetrating peptide corresponding to GPIbα cytoplasmic residues 557–569 reduces VWF-dependent platelet adhesion and profoundly inhibits filopodia formation on VWF matrix, and abolishes shape change in CHO-GPIb-IX cells, demonstrating a functional role of this domain in VWF-dependent adhesion signaling. Cell-penetrating peptide (R9-coupled), platelet adhesion on VWF matrix, CHO-GPIb-IX cell adhesion assays, aggregometry Journal of Thrombosis and Haemostasis Medium 17100656
2003 The GPIbα Gly233Val gain-of-function mutation (platelet-type VWD) enhances formation and increases longevity of the GPIbα–VWF-A1 tether bond (k⁰off mutant 0.67 s⁻¹ vs. native 3.45 s⁻¹) without altering bond strength under applied force, promoting platelet adhesion at shear rates that do not support wild-type binding. Single-molecule kinetics of tether bond formation and dissociation using PT-VWD platelets, flow chamber assays Blood Medium 12637314
1992 The HPA-2 (Ko) alloantigens are located on GPIbα; the HPA-2b (Koa) allele encodes Met145 and HPA-2a (Kob) encodes Thr145, resulting from a C-T polymorphism at position 434 of the coding region. Anti-HPA-2a antibodies inhibit ristocetin-induced agglutination of HPA-2a-positive platelets, placing the epitope near the VWF-binding domain. PCR amplification and DNA sequencing, restriction fragment length polymorphism (RFLP), platelet agglutination inhibition assay Journal of Clinical Investigation High 1346615
2003 The HPA-2 Thr145Met polymorphism affects VWF binding (HPA-2a/Thr145 binds VWF with higher affinity) but does not affect α-thrombin binding to GPIbα, indicating that the dimorphism modulates the conformation of the N-terminal flanking region and first leucine-rich repeat. Recombinant GPIbα N-terminal fragments (AA1-289) from CHO cells, resonant mirror binding studies, monoclonal antibody epitope mapping Arteriosclerosis, Thrombosis, and Vascular Biology Medium 12775575
2009 Prolonged inhibition of protein kinase A (PKA) results in metalloproteinase-dependent GPIbα shedding from platelets; this is reversed by PKA activator forskolin, partially inhibited by calpain inhibitors, and completely blocked by metalloproteinase inhibitor GM6001, indicating PKA activity normally restrains ADAM17-mediated GPIbα cleavage. PKA inhibitor H89, PKA activator (forskolin), GM6001, calpain inhibitors, flow cytometry, VWF-dependent adhesion assays Thrombosis Research Medium 19181367
2013 Mitochondrial permeability transition pore (MPTP) opening triggers mitochondrial ROS production that promotes ADAM17-mediated GPIbα ectodomain shedding; mitochondrial Ca²⁺ uptake via MCU triggers MPTP opening, and both ROS and calpain contribute to shedding downstream of MPTP. MPTP inhibitor/potentiator, mitochondrial Ca²⁺ measurements, MCU inhibitor Ru360, BAPTA-AM, mitochondria-targeted ROS scavenger, calpain inhibitors, flow cytometry Platelets Medium 23909816
2000 Integrity of the leucine-rich repeat region of GPIbα is essential for normal glycosylation and surface expression of the GPIb-IX complex; the Nancy I mutation (deletion of Leu179) causes a 40% reduction in GPIbα molecular weight due to glycosylation deficiency, reduced surface expression, and complete loss of VWF binding and rolling on VWF surfaces. CHO cell transfection with wild-type and mutant GPIbα, flow cytometry, biochemical glycosylation analysis, static adhesion and perfusion assays on VWF Thrombosis and Haemostasis Medium 10928479
2022 The O-glycosylated N-linker of VWF A1 reduces GPIbα binding affinity ~40-fold primarily through its O-glycan moiety and increases A1 thermal stability by raising the energy gap between native and intermediate states; the C-linker also decreases A1 affinity for GPIbα but has no effect on A1 stability or hydrogen-deuterium exchange, indicating distinct allosteric mechanisms for the two linkers. Binding affinity/kinetics measurements, thermodynamics, hydrogen-deuterium exchange (HDX), urea/temperature-induced unfolding, recombinant VWF A1 constructs eLife High 35532124

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature medicine 341 30936549
1998 Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. The Journal of experimental medicine 322 9449713
2004 Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates GPIbalpha shedding from platelets in vitro and in vivo. Circulation research 191 15345652
2006 The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proceedings of the National Academy of Sciences of the United States of America 181 17075060
2011 Desialylation accelerates platelet clearance after refrigeration and initiates GPIbα metalloproteinase-mediated cleavage in mice. Blood 163 22101895
2017 Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nature communications 141 28555620
2003 Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation. Science (New York, N.Y.) 132 12855811
1992 NH2-terminal globular domain of human platelet glycoprotein Ib alpha has a methionine 145/threonine145 amino acid polymorphism, which is associated with the HPA-2 (Ko) alloantigens. The Journal of clinical investigation 131 1346615
1997 Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with an increased risk for stroke. Stroke 108 9227689
2022 S100A8/A9 drives the formation of procoagulant platelets through GPIbα. Blood 83 36026606
2019 Appropriation of GPIbα from platelet-derived extracellular vesicles supports monocyte recruitment in systemic inflammation. Haematologica 80 31467123
2011 Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation). Haematologica 80 21933849
2011 The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies. The Journal of clinical investigation 77 22019589
2001 Platelet glycoprotein Ibalpha HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death. Circulation 71 11514372
2010 von Willebrand factor self-association on platelet GpIbalpha under hydrodynamic shear: effect on shear-induced platelet activation. Blood 69 20696943
2010 High shear-dependent loss of membrane integrity and defective platelet adhesion following disruption of the GPIbα-filamin interaction. Blood 68 21156842
2018 GPIbα is required for platelet-mediated hepatic thrombopoietin generation. Blood 65 29794068
2002 Absence of GPIbalpha is responsible for aberrant membrane development during megakaryocyte maturation: ultrastructural study using a transgenic model. Experimental hematology 65 11937271
2015 Thrombin-induced reactive oxygen species generation in platelets: A novel role for protease-activated receptor 4 and GPIbα. Redox biology 61 26569550
2016 Inhibiting GPIbα Shedding Preserves Post-Transfusion Recovery and Hemostatic Function of Platelets After Prolonged Storage. Arteriosclerosis, thrombosis, and vascular biology 56 27417583
2018 The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions. Blood 52 30429161
2003 Alterations in the intrinsic properties of the GPIbalpha-VWF tether bond define the kinetics of the platelet-type von Willebrand disease mutation, Gly233Val. Blood 51 12637314
2000 Cytoplasmic domains of GpIbalpha and GpIbbeta regulate 14-3-3zeta binding to GpIb/IX/V. Blood 50 10627461
2008 Novel point mutation in a leucine-rich repeat of the GPIbalpha chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard-Soulier syndrome affecting two unrelated families: the N41H variant. Haematologica 46 18815197
2020 Loss of GPVI and GPIbα contributes to trauma-induced platelet dysfunction in severely injured patients. Blood advances 44 32556282
2011 GPIbα regulates platelet size by controlling the subcellular localization of filamin. Blood 43 22174152
2010 Thrombocytopenia in early malaria is associated with GP1b shedding in absence of systemic platelet activation and consumptive coagulopathy. British journal of haematology 42 20955404
2010 GPIbalpha-selective activation of platelets induces platelet signaling events comparable to GPVI activation events. Platelets 40 20367574
1995 VCL, an antagonist of the platelet GP1b receptor, markedly inhibits platelet adhesion and intimal thickening after balloon injury in the rat. Circulation 39 7648675
2018 Comparison between manufacturing sites shows differential adhesion, activation, and GPIbα expression of cryopreserved platelets. Transfusion 38 30312492
2020 Mechanisms of anti-GPIbα antibody-induced thrombocytopenia in mice. Blood 37 32157300
2011 GPVI and GPIbα mediate staphylococcal superantigen-like protein 5 (SSL5) induced platelet activation and direct toward glycans as potential inhibitors. PloS one 37 21552524
2018 Neutrophil infiltration to the brain is platelet-dependent, and is reversed by blockade of platelet GPIbα. Immunology 35 29325217
2010 The mechanism of VWF-mediated platelet GPIbalpha binding. Biophysical journal 35 20713003
2009 Changes in thermodynamic stability of von Willebrand factor differentially affect the force-dependent binding to platelet GPIbalpha. Biophysical journal 34 19619477
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
2013 GpIbα interacts exclusively with exosite II of thrombin. Journal of molecular biology 33 24316004
2003 von Willebrand factor but not alpha-thrombin binding to platelet glycoprotein Ibalpha is influenced by the HPA-2 polymorphism. Arteriosclerosis, thrombosis, and vascular biology 33 12775575
2018 Novel antibodies against GPIbα inhibit pulmonary metastasis by affecting vWF-GPIbα interaction. Journal of hematology & oncology 32 30223883
2004 Real-time PCR genotyping of human platelet alloantigens HPA-1, HPA-2, HPA-3 and HPA-5 is superior to the standard PCR-SSP method. Transfusion medicine (Oxford, England) 32 15569237
2003 Thrombin binding to GPIbalpha induces platelet aggregation and fibrin clot retraction supported by resting alphaIIbbeta3 interaction with polymerized fibrin. Thrombosis and haemostasis 31 12719784
2021 Anti-platelet aggregation of Panax notoginseng triol saponins by regulating GP1BA for ischemic stroke therapy. Chinese medicine 30 33468191
1994 Association of a variable number of tandem repeats (VNTR) in glycoprotein Ib alpha and HPA-2 alloantigens. Thrombosis and haemostasis 30 7900082
2000 Threonine-145/methionine-145 variants of baculovirus produced recombinant ligand binding domain of GPIbalpha express HPA-2 epitopes and show equal binding of von Willebrand factor. Blood 29 10607704
2006 Novel heterozygous missense mutation in the second leucine rich repeat of GPIbalpha affects GPIb/IX/V expression and results in macrothrombocytopenia in a patient initially misdiagnosed with idiopathic thrombocytopenic purpura. European journal of haematology 28 16519708
2012 A novel D235Y mutation in the GP1BA gene enhances platelet interaction with von Willebrand factor in an Iranian family with platelet-type von Willebrand disease. Thrombosis and haemostasis 27 23014764
1992 Localization of the platelet-specific HPA-2 (Ko) alloantigens on the N-terminal globular fragment of platelet glycoprotein Ib alpha. Blood 25 1370207
2019 Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα. Blood advances 24 30700416
1999 Interaction between GPIbalpha and FcgammaIIA receptor in human platelets. Biochemical and biophysical research communications 24 10581159
2018 Dengue Virus Induces the Release of sCD40L and Changes in Levels of Membranal CD42b and CD40L Molecules in Human Platelets. Viruses 23 29976871
2022 The GPIbα intracellular tail - role in transducing VWF- and collagen/GPVI-mediated signaling. Haematologica 22 34134470
2019 cAMP- and cGMP-elevating agents inhibit GPIbα-mediated aggregation but not GPIbα-stimulated Syk activation in human platelets. Cell communication and signaling : CCS 22 31519182
2008 Polymorphisms of the human platelet alloantigens HPA-1, HPA-2, HPA-3, and HPA-4 in ischemic stroke. American journal of hematology 22 18383324
2014 Identification of p.W246L as a novel mutation in the GP1BA gene responsible for platelet-type von Willebrand disease. Seminars in thrombosis and hemostasis 21 24474090
2022 Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP. Blood 20 35157766
2014 Targeting the GPIbα binding site of thrombin to simultaneously induce dual anticoagulant and antiplatelet effects. Journal of medicinal chemistry 20 24635452
2023 Dual roles of fucoidan-GPIbα interaction in thrombosis and hemostasis: implications for drug development targeting GPIbα. Journal of thrombosis and haemostasis : JTH 19 36732162
2020 Increased circulating CD31+/CD42b-EMPs in Perthes disease and inhibit HUVECs angiogenesis via endothelial dysfunction. Life sciences 19 33220290
2006 Inhibition of adhesive and signaling functions of the platelet GPIb-V-IX complex by a cell penetrating GPIbalpha peptide. Journal of thrombosis and haemostasis : JTH 19 17100656
2000 Selectins (CD62L, CD62P) and megakaryocytic glycoproteins (CD41a, CD42b) mediate megakaryocyte-fibroblast interactions in human bone marrow. Leukemia research 19 11077115
2009 Biophysical investigation of GpIbalpha binding to thrombin anion binding exosite II. Biochemistry 18 19591434
1997 Gene frequencies of the HPA-1 and HPA-2 platelet antigen alleles among the Amerindians. Vox sanguinis 18 9358621
2024 GPIbα CAAR T cells function like a Trojan horse to eliminate autoreactive B cells to treat immune thrombocytopenia. Haematologica 17 38299614
2021 GPIbα is the driving force of hepatic thrombopoietin generation. Research and practice in thrombosis and haemostasis 16 33977209
2000 Role of the leucine-rich domain of platelet GPIbalpha in correct post-translational processing--the Nancy I Bernard-Soulier mutation expressed on CHO cells. Thrombosis and haemostasis 16 10928479
2023 GPIbα shedding in platelets is controlled by strict intracellular containment of both enzyme and substrate. Journal of thrombosis and haemostasis : JTH 15 37001816
2019 The Direct Thrombin Inhibitors Dabigatran and Lepirudin Inhibit GPIbα-Mediated Platelet Aggregation. Thrombosis and haemostasis 15 31005062
2004 Effects of a snake venom metalloproteinase, triflamp, on platelet aggregation, platelet-neutrophil and neutrophil-neutrophil interactions: involvement of platelet GPIbalpha and neutrophil PSGL-1. Thrombosis and haemostasis 15 14961160
2024 GPIbα-filamin A interaction regulates megakaryocyte localization and budding during platelet biogenesis. Blood 14 37922495
2019 The impact of GPIbα on platelet-targeted FVIII gene therapy in hemophilia A mice with pre-existing anti-FVIII immunity. Journal of thrombosis and haemostasis : JTH 14 30609275
2011 A A386G biallelic GPIbα gene mutation with anomalous behavior: a new mechanism suggested for Bernard-Soulier syndrome pathogenesis. Haematologica 14 21993687
2001 Compound heterozygosity of the GPIbalpha gene associated with Bernard-Soulier syndrome. Thrombosis and haemostasis 14 11776304
1999 The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar. British journal of cancer 14 10555746
2018 Increased GPIbα shedding from platelets treated with immune thrombocytopenia plasma. International immunopharmacology 13 30445311
2009 Prolonged inhibition of protein kinase A results in metalloproteinase-dependent platelet GPIbalpha shedding. Thrombosis research 13 19181367
2018 Association of Oxidative Stress and Platelet Receptor Glycoprotein GPIbα and GPVI Shedding During Nonsurgical Bleeding in Heart Failure Patients With Continuous-Flow Left Ventricular Assist Device Support. ASAIO journal (American Society for Artificial Internal Organs : 1992) 12 28953486
2014 Exploiting the kinetic interplay between GPIbα-VWF binding interfaces to regulate hemostasis and thrombosis. Blood 12 25293780
2013 The role of mitochondrial permeability transition pore in regulating the shedding of the platelet GPIbα ectodomain. Platelets 12 23909816
2021 The Copenhagen founder variant GP1BA c.58T>G is the most frequent cause of inherited thrombocytopenia in Denmark. Journal of thrombosis and haemostasis : JTH 11 34333846
2012 Diesel exhaust particles impair platelet response to collagen and are associated with GPIbα shedding. Toxicology in vitro : an international journal published in association with BIBRA 11 22542759
2007 Characterization and purification of acidocin 1B, a bacteriocin produced by Lactobacillus acidophilus GP1B. Journal of microbiology and biotechnology 11 18051299
2021 A fibrinolytic snake venom metalloproteinase, mutalysin-II, with antiplatelet activity and targeting capability toward glycoprotein GPIbα and glycoprotein GPVI. Biochimie 10 33548391
2018 A novel germline mutation in GP1BA gene N-terminal domain in monoallelic Bernard-Soulier syndrome. Platelets 10 30332551
2022 Von Willebrand factor A1 domain stability and affinity for GPIbα are differentially regulated by its O-glycosylated N- and C-linker. eLife 9 35532124
2020 Platelet surface GPIbα, activated GPIIb-IIIa, and P-selectin levels in adult veno-arterial extracorporeal membrane oxygenation patients. Platelets 9 33284729
2017 Syk Activity Is Dispensable for Platelet GP1b-IX-V Signaling. International journal of molecular sciences 8 28598382
2016 A novel platelet-type von Willebrand disease mutation (GP1BA p.Met255Ile) associated with type 2B "Malmö/New York" von Willebrand disease. Thrombosis and haemostasis 8 27683759
2007 Platelet GPIbalpha, GPIV and vWF polymorphisms and fatal pre-hospital MI among middle-aged men. Journal of thrombosis and thrombolysis 8 17619827
2022 Guanxinning tablet inhibits the interaction between leukocyte integrin Mac-1 and platelet GPIbα for antithrombosis without increased bleeding risk. Chinese journal of natural medicines 7 36031231
2021 MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex. Frontiers in molecular biosciences 7 33968982
2017 A novel mutation in GP1BA gene leads to mono-allelic Bernard Soulier syndrome form of macrothrombocytopenia. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 7 26849716
2023 Platelet accumulation in an endothelium-coated elastic vein valve model of deep vein thrombosis is mediated by GPIbα-VWF interaction. Frontiers in cardiovascular medicine 6 37180784
2019 T cell-derived soluble glycoprotein GPIbα mediates PGE2 production in human monocytes activated with the vaccine adjuvant MDP. Science signaling 6 31594856
2013 Changes in platelet GPIbα and ADAM17 during the acute stage of atherosclerotic ischemic stroke among Chinese. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 6 23771674
2012 An integrated fragment based screening approach for the discovery of small molecule modulators of the VWF-GPIbα interaction. Chemical communications (Cambridge, England) 6 23072895
2012 Histamine reduces GPIbα-mediated adhesion of platelets to TNF-α-activated vascular endothelium. Thrombosis research 6 23260446
2008 A case of Bernard-Soulier Syndrome due to a homozygous four bases deletion (TGAG) of GPIbalpha gene: lack of GPIbalpha but absence of bleeding. Platelets 6 18791947
2024 Differential Impact In Vivo of Pf4-ΔCre-Mediated and Gp1ba-ΔCre-Mediated Depletion of Cyclooxygenase-1 in Platelets in Mice. Arteriosclerosis, thrombosis, and vascular biology 5 38660804
2024 Reduction of ristocetin-induced platelet aggregation (RIPA) during storage despite plasma renewal: evidence for hemostatic importance of GPIbα shedding. Expert review of hematology 5 38889268
2015 The contribution of von Willebrand factor-GPIbα interactions to persistent aggregate formation in apheresis platelet concentrates. Vox sanguinis 5 26646710

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