Trp(2313)-His(2315) of Factor VIII C2 Domain Is Involved in Membrane Binding STRUCTURE OF A COMPLEX BETWEEN THE C2 DOMAIN AND AN INHIBITOR OF MEMBRANE BINDING

Zhuo Liu, Lin Lin, Cai Yuan, Gerry A. F. Nicolaes, Liqing Chen, Edward J. Meehan, Bruce Furie, Barbara C. Furie, Mingdong Huang*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

33 Citations (Web of Science)

Abstract

Factor VIII (FVIII) plays a critical role in blood coagulation by forming the tenase complex with factor IXa and calcium ions on a membrane surface containing negatively charged phospholipids. The tenase complex activates factor X during blood coagulation. The carboxyl-terminal C2 domain of FVIII is the main membrane-binding and von Willebrand factor-binding region of the protein. Mutations of FVIII cause hemophilia A, whereas elevation of FVIII activity is a risk factor for thromboembolic diseases. The C2 domain-membrane interaction has been proposed as a target of intervention for regulation of blood coagulation. A number of molecules that interrupt FVIII or factor V (FV) binding to cell membranes have been identified through high throughput screening or structure-based design. We report crystal structures of the FVIII C2 domain under three new crystallization conditions, and a high resolution (1.15 angstrom) crystal structure of the FVIII C2 domain bound to a small molecular inhibitor. The latter structure shows that the inhibitor binds to the surface of an exposed beta-strand of the C2 domain, Trp(2313)-His(2315). This result indicates that the Trp(2313)-His(2315) segment is an important constituent of the membrane binding motif and provides a model to understand the molecular mechanism of the C2 domain membrane interaction.
Original languageEnglish
Pages (from-to)8824-8829
JournalJournal of Biological Chemistry
Volume285
Issue number12
DOIs
Publication statusPublished - 19 Mar 2010

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