ArticleCommunications biology2023
Divalent nanobodies to platelet CLEC-2 can serve as agonists or antagonists.
Article in Communications biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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The trial behind it
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Who cites it
8 citing papers in PubMed, 10 citations in OpenAlex.
- Platelet CLEC-2 activation leads to GPIb⍺ shedding: Implications for doxorubicin chemotherapy and thrombosis.The Journal of biological chemistry · 2026Article
- Receptor homodimerization significantly prolongs the lifetime of ligand-induced cross-linking of CLEC-2 but not GPVI.Blood vessels, thrombosis & hemostasis · 2026Article
- sCLEC-2 (Soluble C-Type Lectin-like Receptor 2) as a New Diagnostic Marker of Platelet Activation in Colorectal Cancer Patients-A Preliminary Study.Diagnostics (Basel, Switzerland) · 2026Article
- Hemostasis-Sparing Antiplatelet Therapy: Current Concepts and Emerging Targets in Arterial Thrombosis.Biomolecules & therapeutics · 2026Review
- A minimum valency of 4 is required for robust activation of platelets in flow cytometry by multivalent nanobodies to Glycoprotein VI, C-type lectin-like receptor 2 and Platelet Endothelial Aggregation Receptor 1.Research and practice in thrombosis and haemostasis · 2025Article
- Advancements in the conservation of the conformational epitope of membrane protein immunogens.Frontiers in immunology · 2025Review
- Discovery of Carbonic Anhydrase 9 as a Novel CLEC2 Ligand in a Cellular Interactome Screen.Cells · 2024Article
- Novel therapeutics and emerging technology in haemostasis and thrombosis: highlights from the British society for haemostasis and thrombosis annual meeting.Frontiers in cardiovascular medicine · 2023Article
Corrections and comments
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Authors and funding
17 authors at 7 institutions in 3 countries.
Funding
Abstract
CLEC-2 is a target for a new class of antiplatelet agent. Clustering of CLEC-2 leads to phosphorylation of a cytosolic YxxL and binding of the tandem SH2 domains in Syk, crosslinking two receptors. We have raised 48 nanobodies to CLEC-2 and crosslinked the most potent of these to generate divalent and tetravalent nanobody ligands. Fluorescence correlation spectroscopy (FCS) was used to show that the multivalent nanobodies cluster CLEC-2 in the membrane and that clustering is reduced by inhibition of Syk. Strikingly, the tetravalent nanobody stimulated aggregation of human platelets, whereas the divalent nanobody was an antagonist. In contrast, in human CLEC-2 knock-in mouse platelets, the divalent nanobody stimulated aggregation. Mouse platelets express a higher level of CLEC-2 than human platelets. In line with this, the divalent nanobody was an agonist in high-expressing transfected DT40 cells and an antagonist in low-expressing cells. FCS, stepwise photobleaching and non-detergent membrane extraction show that CLEC-2 is a mixture of monomers and dimers, with the degree of dimerisation increasing with expression thereby favouring crosslinking of CLEC-2 dimers. These results identify ligand valency, receptor expression/dimerisation and Syk as variables that govern activation of CLEC-2 and suggest that divalent ligands should be considered as partial agonists.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.