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J. Biol. Chem., Vol. 278, Issue 12, 10484-10490, March 21, 2003
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From the Edward A. Doisy Department of Biochemistry and Molecular
Biology, St. Louis University School of Medicine,
St. Louis, Missouri 63104
Thrombomodulin (TM) functions as a cofactor to
enhance the rate of protein C activation by thrombin ~1000-fold. The
molecular mechanism by which TM improves the catalytic efficiency of
thrombin toward protein C is not known. Molecular modeling of the
protein C activation based on the crystal structure of thrombin in
complex with the epidermal growth factor-like domains 4, 5, and 6 of TM (TM456) predicts that the binding of TM56 to exosite 1 of thrombin positions TM4 so that a negatively charged region on this domain juxtaposes a positively charged region of protein C. It has been hypothesized that electrostatic interactions between these oppositely charged residues of TM4 and protein C facilitate a proper docking of
the substrate into the catalytic pocket of thrombin. To test this
hypothesis, we have constructed several mutants of TM456 and protein C
in which charges of the putative interacting residues on both TM4
(Asp/Glu) and protein C (Lys/Arg) have been reversed. Results of
TM-dependent protein C activation studies by such a compensatory mutagenesis approach support the molecular model that TM4
interacts with the basic exosite of protein C.
The Fourth Epidermal Growth Factor-like Domain of Thrombomodulin
Interacts with the Basic Exosite of Protein C*
*
This work was supported by NHLBI, National Institutes of
Health, Grants HL 62565 and HL 68571 (to A. R. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Biochemistry
and Molecular Biology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. Tel.: 314-577-8130; Fax:
314-577-8156; E-mail: rezaiear@slu.edu.
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