STRUCTURES OF VON WILLEBRAND FACTOR AND ITS COMPLEXES WITH GLYCOPROTEIN LB AND A

Stanford University, Stanford CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Von Willebrand factor (VWF) plays a pivotal role in thrombosis and hemostasis. It is a polymeric multi-domain molecule, with a subunit of 250 kDa, which interacts with a number of proteins including its platelet receptor, glycoprotein (GP) Ib, and metalloproteinase ADAMTS-13, which specifically cleaves VWF. We propose to study crystal structures of VWF fragments both by themselves and in complex with GP-Ib and ADAMTS-13. We have obtained crystals of a central fragment of VWF, A1-A2-A3, in complex with the inhibitory antibody, NMC4. The A1 domain contains the binding site for the receptor GP-Ib, and the A2 domain contains the cleavage site recognized specifically by ADAMTS-13. The crystals of A1-A2-A3 and NMC4 complex were small and did not diffract. We are optimizing crystallization conditions and plan to bring larger crystals to SSRL for screening and data collection. We have also obtained the ternary complex of the amino terminal domain of GP Ib?, VWF-A1, and thrombin, and are in the process of performing crystallization screening.