title: Trp2313-His2315 of factor VIII C2 domain is involved in membrane binding: structure of a complex between the C2 domain and an inhibitor of membrane binding.
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 A) 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.
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Cai
authors.initials: C
authors.lastname: Yuan
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
authors.forename: Liqing
authors.initials: L
authors.lastname: Chen
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Meehan
authors.forename: Bruce
authors.initials: B
authors.lastname: Furie
authors.forename: Barbara
authors.initials: B
authors.lastname: Furie
authors.forename: Mingdong
authors.initials: M
authors.lastname: Huang
mesh_terms: D001777:Blood Coagulation; D002462:Cell Membrane / Q000378:metabolism*; D018360:Crystallography, X-Ray / Q000379:methods; D005169:Factor VIII / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012306:Risk; D020349:Surface Plasmon Resonance; D013923:Thromboembolism / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry; D014841:von Willebrand Factor / Q000737:chemistry*
chemical_list: D010743:Phospholipids; D014841:von Willebrand Factor; D006639:Histidine; D014364:Tryptophan; D005169:Factor VIII