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.
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.
Liu
Zhuo
Z
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China.
Lin
Lin
L
Yuan
Cai
C
Nicolaes
Gerry A F
GA
Chen
Liqing
L
Meehan
Edward J
EJ
Furie
Bruce
B
Furie
Barbara
B
Huang
Mingdong
M
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*
D010743:Phospholipids; D014841:von Willebrand Factor; D006639:Histidine; D014364:Tryptophan; D005169:Factor VIII