Insights in the molecular steps of the coagulation cascade / Relevance for cell-membrane interactions
Researchers at the Max Planck Institute for Biochemistry in Martinsried/Munich have determined the structure of an important domain of coagulation factor Va. This opens new insights into the molecular details of blood coagulation, as well as in the overall mechanisms of protein-membrane association. The results are reported in Nature 25 November 1999.
An intact circulatory system is vital for all physiological processes. Vascular injuries must be therefore rapidly sealed and repaired. This is achieved through the so-called blood coagulation cascade: several, similarly assembled proteinases (i.e., enzymes, that cleave other proteins) are stepwise specifically activated, in a cumulative domino effect. In the final step of this coagulation cascade, the proteinase thrombin is liberated into the blood stream. As a result of thrombins activities, the soluble plasma protein fibrinogen is converted into fibrin, which spontaneously associates into insoluble polymers. Further, blood platelets are activated by thrombin, and aggregate thereupon. Fibrin and activated platelets constitute the main components of the blood clot, which seals the site of the injury.
A research group, headed by Wolfram Bode in the Department of Structural Research (Director: Prof. Robert Huber) at the Max Planck Institute for Biochemistry in Martinsried/Germany, has solved in the last decade the X-ray structures of thrombin and several inhibitor complexes, as well as other coagulation proteinases (factors IXa and Xa). These results have improved our understanding of the molecular processes leading to blood clotting. On the other hand, the structures of the non-enzymatic cofactors Va and VIIIa were up to now elusive, and therefore their mechanism of membrane association only poorly understood. Investigations conducted at the Duke University (Durham/Nort
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