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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1753-1759. Prepublished online as a Blood First Edition Paper on June 3, 2004; DOI 10.1182/blood-2004-03-1092. This Article Full Text (PDF) All Versions of this Article: 2004-03-1092v1 104/6/1753    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yang, L. Articles by Rezaie, A. R Search for Related Content PubMed PubMed Citation Articles by Yang, L. Articles by Rezaie, A. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 23, 2004 Accepted May 13, 2004 Heparin activated antithrombin interacts with the autolysis loop of target coagulation proteases Likui Yang, Chandrashekhara Manithody, and Alireza R Rezaie* Biochemistry and Molecular Biology, St. Louis University Medical School, St. Louis, MO, USA * Corresponding author; email: rezaiear{at}slu.edu. A unique pentasaccharide fragment of heparin can enhance the reactivity of antithrombin with coagulation proteases factors IXa and Xa by 300-600-fold through a conformational activation of the serpin, without having a significant effect on the reactivity of antithrombin with thrombin. In this study, it was hypothesized that differences in the structure of the autolysis loop of coagulation proteases (residues 143-154 in chymotrypsin numbering) may be responsible for their differential reactivity with the native and heparin activated antithrombin. To test this hypothesis, the autolysis loops of both thrombin and the anticoagulant serine protease activated protein C were replaced with the corresponding loop of factor Xa. Inhibition studies revealed that in contrast to around 1.5-fold difference in the reactivity of thrombin with antithrombin in the absence and presence of pentasaccharide, the difference in reactivity was increased to around 37-fold for the mutant thrombin. In the case of the activated protein C mutant, similar to factor Xa, pentasaccharide accelerated the reaction 375-fold. These results suggest that structural differences in the autolysis loop of coagulation proteases play a key role in their differential reactivity with the native and heparin activated conformations of antithrombin. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Izaguirre, A. R. Rezaie, and S. T. Olson Engineering Functional Antithrombin Exosites in {alpha}1-Proteinase Inhibitor That Specifically Promote the Inhibition of Factor Xa and Factor IXa J. Biol. Chem., January 16, 2009; 284(3): 1550 - 1558. [Abstract] [Full Text] [PDF] A. R. Rezaie, C. Manithody, and L. Yang Identification of Factor Xa Residues Critical for Interaction with Protein Z-dependent Protease Inhibitor: BOTH ACTIVE SITE AND EXOSITE INTERACTIONS ARE REQUIRED FOR INHIBITION J. Biol. Chem., September 23, 2005; 280(38): 32722 - 32728. [Abstract] [Full Text] [PDF]

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