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Thrombomodulin structure and function
1Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. esadler@imgate.wustl.edu
Thrombomodulin is protein cofactor expressed on endothelial cell surfaces that modifies the substrate specificity of thrombin, apparently by an allosteric mechanism. The thrombin-thrombomodulin complex activates protein C, initiating an essential anticoagulant pathway. The cofactor function of membrane-associated thrombomodulin requires the last three of six tandemly repeated EGF-like domains (numbers 4, 5, and 6), as well as a Ser/Thr-rich spacer between EGF-like domain 6 and the transmembrane domain. The Ser/Thr-rich domain is variably modified with a chondroitin sulfate chain that influences the affinity of thrombin binding and the calcium ion dependence of cofactor function. The structure of EGF-like domain 4 has been determined by NMR spectroscopy, and the structure of a complex between thrombin and a peptide from thrombomodulin EGF-like domain 5 was determined by X-ray crystallography. These structures are small steps toward an understanding of how thrombomodulin regulates thrombin.
Thrombomodulin is protein cofactor expressed on endothelial cell surfaces that modifies the substrate specificity of thrombin, apparently by an allosteric mechanism. The thrombin-thrombomodulin complex activates protein C, initiating an essential anticoagulant pathway. The cofactor function of membrane-associated thrombomodulin requires the last three of six tandemly repeated EGF-like domains (numbers 4, 5, and 6), as well as a Ser/Thr-rich spacer between EGF-like domain 6 and the transmembrane domain. The Ser/Thr-rich domain is variably modified with a chondroitin sulfate chain that influences the affinity of thrombin binding and the calcium ion dependence of cofactor function. The structure of EGF-like domain 4 has been determined by NMR spectroscopy, and the structure of a complex between thrombin and a peptide from thrombomodulin EGF-like domain 5 was determined by X-ray crystallography. These structures are small steps toward an understanding of how thrombomodulin regulates thrombin.