GPVI (Glycoprotein VI) interaction with fibrinogen is mediated by avidity and the fibrinogen αC-region

Rui-Gang Xu, Julia Gauer, Stephen Baker, Alexandre Slater, Eleyna Martin, Helen McPherson, Cedric Duval, Iain Manfield, Arkadiusz Bonna, Steve Watson, Robert A. S. Ariëns

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Abstract

Objective: GPVI (glycoprotein VI) is a key molecular player in collagen-induced platelet signaling and aggregation. Recent evidence indicates that it also plays important role in platelet aggregation and thrombus growth through interaction with fibrin(ogen). However, there are discrepancies in the literature regarding whether the monomeric or dimeric form of GPVI binds to fibrinogen at high affinity. The mechanisms of interaction are also not clear, including which region of fibrinogen is responsible for GPVI binding. We aimed to gain further understanding of the mechanisms of interaction at molecular level and to identify the regions on fibrinogen important for GPVI binding.

Approach and Results: Using multiple surface- and solution-based protein-protein interaction methods, we observe that dimeric GPVI binds to fibrinogen with much higher affinity and has a slower dissociation rate constant than the monomer due to avidity effects. Moreover, our data show that the highest affinity interaction of GPVI is with the αC-region of fibrinogen. We further show that GPVI interacts with immobilized fibrinogen and fibrin variants at a similar level, including a nonpolymerizing fibrin variant, suggesting that GPVI binding is independent of fibrin polymerization.

Conclusions: Based on the above findings, we conclude that the higher affinity of dimeric GPVI over the monomer for fibrinogen interaction is achieved by avidity. The αC-region of fibrinogen appears essential for GPVI binding. We propose that fibrin polymerization into fibers during coagulation will cluster GPVI through its αC-region, leading to downstream signaling, further activation of platelets, and potentially stimulating clot growth.
Original languageEnglish
Pages (from-to)1092-1104
Number of pages13
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume41
Issue number3
Early online date21 Jan 2021
DOIs
Publication statusPublished - Mar 2021

Keywords

  • fibrin
  • fibrinogen
  • glycoprotein
  • platelet aggregation
  • thrombosis

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