How Na+ activates thrombin--a review of the functional and structural data.
How Na+ activates thrombin--a review of the functional and structural data.
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DOI：
10.1515/bc.2008.113
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发表时间：
2008-08
影响因子：
3.7
通讯作者：
Huntington JA
中科院分区：
文献类型：
--
作者：
Huntington JA
Thrombin is often referred to as the ultimate blood coagulation protease. This is true in both senses: it is the final protease generated in the series of proteolytic events known as the blood coagulation cascade, and it is the effector of clot formation, cleaving over twelve different substrates and interacting with at least six cofactors. Regulation of thrombin activity is thus of great relevance to determining the correct haemostatic balance, with dysregulation leading to bleeding or thrombosis. One of the most enigmatic and controversial regulators of thrombin activity is the monovalent cation Na+. When bound to Na+, thrombin adopts a ‘fast’ conformation which cleaves all procoagulant substrates more rapidly, and when free of Na+, thrombin reverts to a ‘slow’ state which preferentially activates the protein C anticoagulant pathway. Thus, Na+ binding allosterically modulates the activity of thrombin and helps determine the haemostatic balance. Over the last 30 years there has been a great deal of research into the structural basis of thrombin allostery. Biochemical and mutagenesis studies established which regions and residues are involved in the slow→fast conformational change, and recently several crystal structures of the putative slow form have been solved. In this article I review the biochemical and crystallographic data to see if we are any closer to understanding the conformational basis of the Na+ activation of thrombin.
