title: The interaction of integrin αIIbβ3 with fibrin occurs through multiple binding sites in the αIIb β-propeller domain.
abstract: The currently available antithrombotic agents target the interaction of platelet integrin αIIbβ3 (GPIIb-IIIa) with fibrinogen during platelet aggregation. Platelets also bind fibrin formed early during thrombus growth. It was proposed that inhibition of platelet-fibrin interactions may be a necessary and important property of αIIbβ3 antagonists; however, the mechanisms by which αIIbβ3 binds fibrin are uncertain. We have previously identified the γ370-381 sequence (P3) in the γC domain of fibrinogen as the fibrin-specific binding site for αIIbβ3 involved in platelet adhesion and platelet-mediated fibrin clot retraction. In the present study, we have demonstrated that P3 can bind to several discontinuous segments within the αIIb β-propeller domain of αIIbβ3 enriched with negatively charged and aromatic residues. By screening peptide libraries spanning the sequence of the αIIb β-propeller, several sequences were identified as candidate contact sites for P3. Synthetic peptides duplicating these segments inhibited platelet adhesion and clot retraction but not platelet aggregation, supporting the role of these regions in fibrin recognition. Mutant αIIbβ3 receptors in which residues identified as critical for P3 binding were substituted for homologous residues in the I-less integrin αMβ2 exhibited reduced cell adhesion and clot retraction. These residues are different from those that are involved in the coordination of the fibrinogen γ404-411 sequence and from auxiliary sites implicated in binding of soluble fibrinogen. These results map the binding of fibrin to multiple sites in the αIIb β-propeller and further indicate that recognition specificity of αIIbβ3 for fibrin differs from that for soluble fibrinogen.
authors: From the Center for Metabolic and Vascular Biology and.
authors: Nataly P
authors: NP
authors: Podolnikova
authors: Sergiy
authors: S
authors: Yakovlev
authors: Valentin P
authors: VP
authors: Yakubenko
authors: Xu
authors: X
authors: Wang
authors: Oleg V
authors: OV
authors: Gorkun
authors: Tatiana P
authors: TP
authors: Ugarova
mesh_terms: D001665:Binding Sites; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005337:Fibrin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005340:Fibrinogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D039421:Integrin alpha2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D010973:Platelet Adhesiveness / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: C056564:ITGA2B protein, human; D039421:Integrin alpha2; D016177:Macrophage-1 Antigen; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005337:Fibrin; D005340:Fibrinogen
keywords: Adhesion; Clot Retraction; Fibrin; Fibrinogen; Integrin; Platelets