Ligand binding shuttles thrombin along a continuum of zymogen- and proteinase-like states.

The Journal of Biological Chemistry
Parvathi KamathSriram Krishnaswamy

Abstract

The critical and multiple roles of thrombin in blood coagulation are regulated by ligands and cofactors. Zymogen activation imparts proteolytic activity to thrombin and also affects the binding of ligands to its two principal exosites. We have used the activation peptide fragment 1.2 (F12), a ligand for anion-binding exosite 2, to probe the zymogenicity of thrombin by isothermal titration calorimetry. We show that F12 binding is sensitive to subtle aspects of proteinase formation beyond simply reporting on zymogen cleavage. Large thermodynamic differences in F12 binding distinguish between a series of thrombin species poised along the transition of zymogen to proteinase. Active-site ligands transitioned a zymogen-like state to a proteinase-like state. Conversely, removal of Na(+) converted proteinase-like thrombin to a more zymogen-like form. Thrombin mutants, with deformed x-ray structures, previously considered to be emblematic of specific regulated states of the enzyme, are instead shown to be variously zymogen-like and can be made proteinase-like by active-site ligation. Thermodynamic linkage between anion-binding exosite 2, the Na(+)-binding site, and the active site arises from interconversions of thrombin between a conti...Continue Reading

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