Poster Presentation 9th General Meeting of the International Proteolysis Society 2015

Molecular model of human prothrombinase complex based on the crystal structure of Pseutarin C (#167)

Fatma Isık Ustok 1 , Anja Pomowski 1 , James A. Huntington 1
  1. Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom

Thrombin, the key protease in the coagulation cascade, is generated from prothrombin through cleavage at two sites.  Prothrombinase, a complex that assembles through reversible interactions between a serine protease, factor Xa and a cofactor protein, factor Va on negatively charged phospholipid membranes, is responsible for the conversion of zymogen precursor prothrombin to active protease thrombin.  The balance between bleeding and thrombosis is largely based on thrombin formation, which in turn depends on the function of the prothrombinase complex. Until recently, very limited structural information was available on complex assembly, and the molecular models built to date used partial structures combined with biochemical data.  Our group solved the crystal structure of Pseutarin C, a stable prothrombinase complex preassembled in the venom gland of the Australian brown snake (Pseudonaja textilis).  Here we present the homology model of human prothrombinase complex based on the crystal structure of Pseutarin C.  The interface is complementary in shape and charge, and consistent with much of the published biochemical data.