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M512082200v1
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Papers In Press, published online ahead of print January 20, 2006
J. Biol. Chem, 10.1074/jbc.M512082200
Submitted on November 9, 2005
Revised on January 18, 2006
Accepted on January 20, 2006

Murine thrombin lacks Na+ activation but retains high catalytic activity

Leslie A. Bush, Ryan W. Nelson, and Enrico Di Cera

Dept. of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St Louis, MO 63110

Corresponding Author: enrico{at}wustl.edu

Human thrombin utilizes Na+ as a driving force for the cleavage of substrates mediating its procoagulant, prothrombotic and signaling functions. Murine thrombin has Asp-222 in the Na+ binding site of the human enzyme replaced by Lys. The charge reversal substitution abrogates Na+ activation, that is partially restored with the K222D mutation, and ensures high activity even in the absence of Na+. This property makes the murine enzyme more resistant to the effect of mutations that destabilize Na+ binding and shift thrombin to its anticoagulant slow form. Compared to the human enzyme, murine thrombin cleaves fibrinogen and protein C with similar kcat/Km values, but activates PAR1 and PAR4 with kcat/Km values 4-fold and 26-fold higher. The significantly higher specificity constant toward PAR4 accounts for the dominant role of this receptor in platelet activation in the mouse. Murine thrombin can also cleave substrates carrying Phe at P1, which potentially broadens the repertoire of molecular targets available to the enzyme in vivo.


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