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Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes

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Title: Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes
Author(s): Schedin-Weiss, Sophia; Richard, Benjamin; Olson, Steven T.
Subject(s): heparin antithrombin
Abstract: The serpin, antithrombin, requires allosteric activation by a sequencespecific pentasaccharide unit of heparin or heparan sulfate glycosaminoglycans to function as an anticoagulant regulator of blood clotting proteases. Surprisingly, X-ray structures have shown that the pentasaccharide produces similar inducedfit changes in the heparin binding site of native and latent antithrombin despite large differences in the heparin affinity and global conformation of these two forms. Here we present kinetic evidence for similar induced-fit mechanisms of pentasaccharide binding to native and latent antithrombins and kinetic simulations which together support a three-step mechanism of allosteric activation of native antithrombin involving two successive conformational changes. Equilibrium binding studies of pentasaccharide interactions with native and latent antithrombins and the salt dependence of these interactions suggest that each conformational change is associated with distinct spectroscopic changes and is driven by a progressively better fit of the pentasaccharide in the binding site. The observation that variant antithrombins that cannot undergo the second conformational change bind the pentasaccharide like latent antithrombin and are partially activated suggests that both conformational changes contribute to allosteric activation, in agreement with a recently proposed model of allosteric activation.
Issue Date: 2010-12-15
Publisher: Elsevier
Citation Info: Schedin-Weiss, S., Richard, B., & Olson, S. T. 2010. Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes. Archives of Biochemistry and Biophysics, 504(2): 169-176. DOI: 10.1016/j.abb.2010.08.021
Type: Article
Description: Post print version of article may differ from published version. The definitive version is available through Elsevier at DOI: 10.1016/j.abb.2010.08.021
URI: http://hdl.handle.net/10027/7641
ISSN: 0003-9861
Date Available in INDIGO: 2011-05-25
 

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