Snake venom prothrombin activators homologous to blood coagulation factor Xa.
We have recently determined the complete amino acid sequence of trocarin, a group D prothrombin activator from the venom of Tropidechis carinatus (Australian rough-scaled snake). This proteinase is both functionally and structurally similar to mammalian blood coagulation factor Xa. It shows approximately 70% homology and possesses the characteristic Gla domain, two EGF domains and serine proteinase domain. To examine structure-function relationships, we generated a molecular model of trocarin based on a human factor Xa des-Gla crystal structure (1xka) as template. Based on known sites of interaction between mammalian factor Xa, factor Va and prothrombin, structure-function relationships of trocarin were explored. Unlike factor Xa, trocarin is glycosylated and has a large carbohydrate moiety at the entrance to its active site pocket. This might contribute to differences observed in the kinetics of hydrolysis of synthetic substrates by trocarin as compared to human factor Xa. A Ca(2+)-binding loop present in the heavy chain of factor Xa also seems to be lost in trocarin. In addition to its role in hemostasis, factor Xa shows other biological effects, including inflammation via its interaction with effector protease receptor-1 (EPR-1). Interestingly, the EPR-1 recognition site is distinctly different in trocarin, the functional consequences of which are being investigated.
Joseph
J S
JS
Department of Biochemistry, Faculty of Medicine, National University of Singapore, 14 Science Drive, Singapore 117543.
Kini
R M
RM
D000818:Animals; D001665:Binding Sites; D003029:Coagulants; D015951:Factor Xa / Q000737:chemistry / Q000235:genetics; D006801:Humans; D011499:Protein Processing, Post-Translational; D011516:Prothrombin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D012910:Snake Venoms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D003029:Coagulants; D012910:Snake Venoms; C120393:trocarin; D011516:Prothrombin; D015951:Factor Xa