Thrombomodulin structure and function.
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.
Sadler
J E
JE
Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. esadler@imgate.wustl.edu
D000595:Amino Acid Sequence; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011486:Protein C / Q000378:metabolism; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000737:chemistry* / Q000502:physiology
D011486:Protein C; D018180:Thrombomodulin; D013917:Thrombin