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GPVI (Glycoprotein VI) Interaction With Fibrinogen Is Mediated by Avidity and the Fibrinogen αC-Region.
Xu, Rui-Gang; Gauer, Julia S; Baker, Stephen R; Slater, Alexandre; Martin, Eleyna M; McPherson, Helen R; Duval, Cédric; Manfield, Iain W; Bonna, Arkadiusz M; Watson, Steve P; Ariëns, Robert A S.
Afiliação
  • Xu RG; Discovery and Translational Science Department, Institute of Cardiovascular and Metabolic Medicine (R.-G.X., J.S.G., S.R.B., H.R.M., C.D., R.A.S.A.).
  • Gauer JS; Discovery and Translational Science Department, Institute of Cardiovascular and Metabolic Medicine (R.-G.X., J.S.G., S.R.B., H.R.M., C.D., R.A.S.A.).
  • Baker SR; Discovery and Translational Science Department, Institute of Cardiovascular and Metabolic Medicine (R.-G.X., J.S.G., S.R.B., H.R.M., C.D., R.A.S.A.).
  • Slater A; Department of Physics, Wake Forest University, Winston Salem, NC (S.R.B.).
  • Martin EM; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, United Kingdom (A.S., E.M.M., S.P.W.).
  • McPherson HR; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, United Kingdom (A.S., E.M.M., S.P.W.).
  • Duval C; Discovery and Translational Science Department, Institute of Cardiovascular and Metabolic Medicine (R.-G.X., J.S.G., S.R.B., H.R.M., C.D., R.A.S.A.).
  • Manfield IW; Discovery and Translational Science Department, Institute of Cardiovascular and Metabolic Medicine (R.-G.X., J.S.G., S.R.B., H.R.M., C.D., R.A.S.A.).
  • Bonna AM; School of Molecular and Cellular Biology, Faculty of Biological Sciences (I.W.M.), University of Leeds, United Kingdom.
  • Watson SP; Department of Biochemistry, University of Cambridge, United Kingdom (A.M.B.).
  • Ariëns RAS; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, United Kingdom (A.S., E.M.M., S.P.W.).
Arterioscler Thromb Vasc Biol ; 41(3): 1092-1104, 2021 03.
Article em En | MEDLINE | ID: mdl-33472402
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. Graphic Abstract A graphic abstract is available for this article.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Fibrinogênio / Glicoproteínas da Membrana de Plaquetas Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Fibrinogênio / Glicoproteínas da Membrana de Plaquetas Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article