Murine thrombin lacks Na+ activation but retains high catalytic activity

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

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

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, which 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 with 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- and 26-fold higher, respectively. 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.

Original languageEnglish (US)
Pages (from-to)7183-7188
Number of pages6
JournalJournal of Biological Chemistry
Volume281
Issue number11
DOIs
StatePublished - Mar 17 2006

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