Integrin αIIbβ3 plays a critical role in platelet aggregation through its interaction with fibrinogen. Elucidation of the mechanisms of αIIbβ3- fibrinogen interaction is critical to understanding hemostasis and thrombosis. Here we report that mutations of Gly-184, Tyr-189, Tyr-190, Phe- 191, and Gly-193 within the predicted turn structure of the third amino- terminal repeat of αIIb significantly block binding of αIIbβ3 to soluble fibrinogen. These mutations also block binding of αIIbβ3 to ligand-mimetic monoclonal antibodies PAC-1, OP-G2, LJ-CP3, which have an RGD-related RYD sequence in their antigen-binding sites. These mutations do not significantly affect the expression of αIIbβ3, in contrast to most of the natural αIIb mutations occurring in Glanzmann's thrombasthenic patients. The data suggest that these residues are critically involved in αIIbβ3-ligand interactions.
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