The role of tryptophan residues in heparin-antithrombin interactions |
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Authors: | George I. Karp James A. Marcum Robert D. Rosenberg |
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Affiliation: | 1. Department of Biology/Whitaker College, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139 U.S.A.;2. The Dana Farber Cancer Institute, and the Departments of Medicine, Harvard Medical School and Beth Israel Hospital, Boston, Massachusetts 02115 U.S.A. |
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Abstract: | A single tryptophan residue on antithrombin has been modified with dimethyl-(2-hydroxy-5-nitrobenzyl)sulfonium bromide. This alteration led to a 500-fold reduction in the heparin-dependent acceleration of thrombin-modified antithrombin interactions, as well as a 10-fold decrease in the avidity of the modified protease inhibitor for mucopolysaccharide. Preincubation of antithrombin with the octasaccharide binding domain of heparin prior to treatment with dimethyl-(2-hydroxy-5-nitrobenzyl)sulfonium bromide was able to suppress modification of the critical tryptophan and preserve the functional capacities of the protease inhibitor. Fluorescence quenching experiments indicated that the modifiable tryptophan groups of antithrombin were exposed to the solvent environment. Based upon these data, it was proposed that the loss of “heparin cofactor” activity of antithrombin must be predominantly due to an inability of the modified protease inhibitor to undergo a conformational transition required for mucopolysaccharide-dependent “activation” of the macromolecule. |
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Keywords: | To whom correspondence should be addressed. |
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