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Thrombomodulin structure and function

J E Sadler1

  • 1Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. esadler@imgate.wustl.edu

Thrombosis and Haemostasis
|July 1, 1997
PubMed
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Thrombomodulin, a protein cofactor on endothelial cells, regulates blood clotting by activating protein C. Its structure, particularly EGF-like domains 4-6, is crucial for this anticoagulant function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hematology

Background:

  • Thrombomodulin is an endothelial cell surface protein cofactor.
  • It modifies thrombin's substrate specificity via an allosteric mechanism.
  • The thrombin-thrombomodulin complex initiates the protein C anticoagulant pathway.

Purpose of the Study:

  • To elucidate the structural basis of thrombomodulin's cofactor function.
  • To understand how thrombomodulin regulates thrombin activity.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy to determine the structure of EGF-like domain 4.
  • X-ray crystallography to determine the structure of a thrombin-thrombomodulin EGF-like domain 5 peptide complex.

Main Results:

Related Experiment Videos

  • The last three EGF-like domains (4, 5, and 6) and a Ser/Thr-rich spacer are essential for thrombomodulin's cofactor function.
  • A chondroitin sulfate chain on the Ser/Thr-rich domain affects thrombin binding affinity and calcium ion dependence.
  • Structural data for key thrombomodulin domains provide insights into its mechanism.

Conclusions:

  • Thrombomodulin's structure, particularly its EGF-like domains and glycosylation, is critical for its anticoagulant role.
  • Understanding these structural elements advances knowledge of thrombomodulin's regulation of thrombin.