Structure-function relationship of the platelet glycoprotein VI (GPVI) receptor: does it matter if it is a dimer or monomer?

Abstract

GPVI is a critical signaling receptor responsible for collagen-induced platelet activation and a promising anti-thrombotic target in conditions such as coronary artery thrombosis, ischemic stroke, and atherothrombosis. This is due to the ability to block GPVI while having minimal effects on hemostasis, making it a more attractive target over current dual-antiplatelet therapy (DAPT) with acetyl salicylic acid and P2Y₁₂ inhibitors where bleeding can be a problem. Our current understanding of how the structure of GPVI relates to function is inadequate and recent studies contradict each other. In this article, we summarize the structure-function relationships underlying the activation of GPVI by its major ligands, including collagen, fibrin(ogen), snake venom toxins and charged exogenous ligands such as diesel exhaust particles. We argue that contrary to popular belief dimerization of GPVI is not required for binding to collagen but serves to facilitate binding through increased avidity, and that GPVI is expressed as a mixture of monomers and dimers on resting platelets, with binding of multivalent ligands inducing higher order clustering.

Keywords:

• GPVI
• Dimerization
• Platelets
• Ligands
• Structure-function

Acknowledgements

We acknowledge support from the British Heart Foundation (RG/13/18/30563) and Wellcome Trust (204951/Z/16Z). JC and FD are supported by COMPARE studentships. YC is supported by the European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement (No. 766118). SPW is a British Heart Foundation Professor (CH 03/003). We thank Natalie Poulter and Mike Tomlinson for critical discussions.

Declaration of interest

The authors report no conflict of interest.

Additional information

Funding

This work was supported by the British Heart Foundation [RG/13/18/30563]; Centre of Membrane Proteins and Receptors (COMPARE) [PhD studentships]; European Union’s Horizon 2020 research and innovation program [Marie Sklodowska-Curie grant agreement (No. 766118]; Wellcome Trust [204951/Z/16Z].