Structure of the C2 domain of human factor VIII at 1.5 A resolution.

Nature 1999 Nov;402(6760):439-42

Program in Structural Biology, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

Human factor VIII is a plasma glycoprotein that has a critical role in blood coagulation. Factor VIII circulates as a complex with von Willebrand factor. After cleavage by thrombin, factor VIIIa associates with factor IXa at the surface of activated platelets or endothelial cells. This complex activates factor X (refs 6, 7), which in turn converts prothrombin to thrombin in the presence of factor Va (refs 8, 9). The carboxyl-terminal C2 domain of factor VIII contains sites that are essential for its binding to von Willebrand factor and to negatively charged phospholipid surfaces. Here we report the structure of human factor VIII C2 domain at 1.5 A resolution. The structure reveals a beta-sandwich core, from which two beta-turns and a loop display a group of solvent-exposed hydrophobic residues. Behind the hydrophobic surface lies a ring of positively charged residues. This motif suggests a mechanism for membrane binding involving both hydrophobic and electrostatic interactions. The structure explains, in part, mutations in the C2 region of factor VIII that lead to bleeding disorders in haemophilia A.

Download full-text PDF

Source
http://dx.doi.org/10.1038/46601DOI Listing
November 1999

Publication Analysis

Top Keywords

factor viii
24
factor
12
human factor
12
willebrand factor
8
von willebrand
8
viii
6
converts prothrombin
4
thrombin presence
4
hydrophobic residues
4
prothrombin thrombin
4
residues hydrophobic
4
solvent-exposed hydrophobic
4
factor carboxyl-terminal
4
carboxyl-terminal domain
4
presence factor
4
factor turn
4
cells complex
4
endothelial cells
4
ring positively
4
platelets endothelial
4

References

(Supplied by CrossRef)

WH Kane et al.
Blood 1988

RJ Kaufman et al.
Annu. Rev. Med. 1992

PJ Fay et al.
J. Biol. Chem. 1991

PA Foster et al.
Blood 1990

EJ Duffy et al.
J. Biol. Chem. 1992

EJ Duffy et al.
J. Biol. Chem. 1992

G van Dieijen et al.
J. Biol. Chem. 1981

S Krishnaswamy et al.
Methods Enzymol. 1993

KG Mann et al.
Blood 1990

EL Saenko et al.
J. Biol. Chem. 1995

Similar Publications