Abstract
The serine protease thrombin proteolytically activates blood coagulation factor XIII by cleavage at residue Arg(37); factor XIII in turn cross-links fibrin molecules and gives mechanical stability to the blood clot. The 2.0-A resolution x-ray crystal structure of human alpha-thrombin bound to the factor XIII-(28-37) decapeptide has been determined. This structure reveals the detailed atomic level interactions between the factor XIII activation peptide and thrombin and provides the first high resolution view of this functionally important part of the factor XIII molecule. A comparison of this structure with the crystal structure of fibrinopeptide A complexed with thrombin highlights several important determinants of thrombin substrate interaction. First, the P1 and P2 residues must be compatible with the geometry and chemistry of the S1 and S2 specificity sites in thrombin. Second, a glycine in the P5 position is necessary for the conserved substrate conformation seen in both factor XIII-(28-37) and fibrinopeptide A. Finally, the hydrophobic residues, which occupy the aryl binding site of thrombin determine the substrate conformation further away from the catalytic residues. In the case of factor XIII-(28-37), the aryl binding site is shared by hydrophobic residues P4 (Val(34)) and P9 (Val(29)). A bulkier residue in either of these sites may alter the substrate peptide conformation.
Highlights
The serine protease thrombin proteolytically activates blood coagulation factor XIII by cleavage at residue Arg37; factor XIII in turn cross-links fibrin molecules and gives mechanical stability to the blood clot
The P1 and P2 residues must be compatible with the geometry and chemistry of the S1 and S2 specificity sites in thrombin
A glycine in the P5 position is necessary for the conserved substrate conformation seen in both factor XIII-(28 –37) and fibrinopeptide A
Summary
The serine protease thrombin proteolytically activates blood coagulation factor XIII by cleavage at residue Arg; factor XIII in turn cross-links fibrin molecules and gives mechanical stability to the blood clot. The 2.0-Å resolution x-ray crystal structure of human ␣-thrombin bound to the factor XIII-(28 –37) decapeptide has been determined. This structure reveals the detailed atomic level interactions between the factor XIII activation peptide and thrombin and provides the first high resolution view of this functionally important part of the factor XIII molecule. Thrombin is the most potent stimulator of platelet aggregation [5] Thrombin achieves this diverse yet specific recognition of substrates with a deep active site cleft and by exploiting an apolar binding site near the catalytic residues as well as an anion binding exosite distant from the active site cleft [6]. In the present study a 2.0-Å resolution crystal structure of the factor XIII activation peptide, encompassing residues 28 –37, complexed to human ␣-thrombin, sheds light on further details of thrombin-substrate interactions. The activated enzyme catalyzes the formation of ␥-glutamyl-⑀-lysyl amide cross-links between polypeptide chains in adjacent fibrin molecules, rendering the blood clot mechanically stable and resistant to fibrinolysis
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