PDBsum entry: 1d7p

Blood clotting

PDB id: 1d7p

Contents

Protein chain

159 a.a. *

Ligands

SO4 ×2

CYS

GOL

Waters ×247

* Residue conservation analysis

PDB id:

1d7p

Name:

Blood clotting

Title:

Crystal structure of the c2 domain of human factor viii at 1 resolution at 1.5 a

Structure:

Coagulation factor viii precursor. Chain: m. Fragment: c2-domain. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932

Resolution:

1.50Å R-factor: 0.205 R-free: 0.215

Authors:

K.P.Pratt,B.W.Shen,B.L.Stoddard

Key ref:

K.P.Pratt et al. (1999). Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature, 402, 439-442. PubMed id: 10586887 DOI: 10.1038/46601

Date:

19-Oct-99 Release date: 01-Dec-99

Protein chain

P00451  (FA8_HUMAN) -  Coagulation factor VIII

Seq: 2351 a.a.

Struc: 159 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 

• Biological process: cell adhesion (2 terms)

DOI no: 10.1038/46601

Nature 402:439-442 (1999)

PubMed id: 10586887

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

K.P.Pratt, B.W.Shen, K.Takeshima, E.W.Davie, K.Fujikawa, B.L.Stoddard.

ABSTRACT

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.

Selected figure(s)

Figure 1.
Figure 1 Ribbon diagram and proposed membrane-binding mode. a, The structure consists of 19 -strands, including an eight-stranded -sandwich core. Two of the three -hairpins and an additional loop extend beyond the core fold. These regions, which are predominantly hydrophobic, flank a pair of positively charged clefts. b, The putative membrane-binding surface includes M2199 and F2200 from the first turn, L2251 and L2252 from the second turn, and V2223 from the adjacent loop. These hydrophobic residues and a belt of basic residues partition on either side of the horizontal grey line which indicates the putative polar/nonpolar boundary of a phospholipid bilayer surface.

Figure 2.
Figure 2 Molecular surface of the factor VIII C2 domain. Left panel, orientation similar to that in Fig. 1a; right panel, the structure is rotated by 90° to look directly into the bottom of the molecule. Blue represents positively charged residues; red, negatively charged; white, uncharged. Note the uncharged protrusions formed by the turns and loops shown in Fig. 1. W2313 also appears to participate in this hydrophobic surface. A 'ring' of solvent-accessible, positively charged residues lies directly behind this surface. The hydrophobic patch on the top of the molecule is also seen in the left panel.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1999, 402, 439-442) copyright 1999.

Figures were selected by an automated process.