. VWF A1 and A1(R545A) bound to platelets with affinities and rate constants similar to those for binding to GPIb␣-CaM, and botrocetin had the expected positively cooperative effect on the binding of VWF A1 to GPIb␣-CaM. Therefore, allosteric regulation by botrocetin of VWF A1 binding to GPIb␣, and the increased binding affinity caused by mutations in VWF or GPIb␣, are reproduced by isolated structural domains. The substantial increase in k on caused by mutations in either A1 or GPIb␣ suggests that productive interaction requires rate-limiting conformational changes in both binding sites. The exceptionally slow k on and k off provide important new constraints on models for rapid platelet tethering at high wall shear rates.

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