CRYSTAL-STRUCTURE OF THE VON-WILLEBRAND-FACTOR A1 DOMAIN AND IMPLICATIONS FOR THE BINDING OF PLATELET GLYCOPROTEIN IB

von Willebrand Factor (vWF) is a multimeric protein that mediates plat elet adhesion to exposed subendothelium at sites of vascular injury un der conditions of high flow/shear. The Al domain of vWF (vWF-A1) forms the principal binding site for platelet glycoprotein Ib (GpIb), an in teraction that is tightly regulated. We report here the crystal struct ure of the vWF-A1 domain at 2.3-Angstrom resolution. As expected, the overall fold is similar to that of the vWF-A3 and integrin I domains. However, the structure also contains N- and C-terminal arms that wrap across the lower surface of the domain. Unlike the integrin I domains, vWF-A1 does not contain a metal ion-dependent adhesion site motif. An alysis of the available mutagenesis data suggests that the activator b otrocetin binds to the right-hand face of the domain containing helice s alpha 5 and alpha 6. Possible binding sites for GpIb are the front a nd upper surfaces of the domain. Natural mutations that lead to consti tutive GpIb binding (von Willebrand type IIb disease) cluster in a dif ferent site, at the interface between the lower surface and the termin al arms, suggesting that they disrupt a regulatory region rather than forming part of the primary GpIb binding site. A possible pathway for propagating structural changes from the regulatory region to the ligan d-binding surface is discussed.