Thrombomodulin: From haemostasis to inflammation and tumourigenesis

Thrombomodulin (TM), a transmembrane endothelial receptor, participates in coagulation, in inflammation, in cancer and plays a role during embryogenesis. The nucleotide sequence of the TM cDNA allows the structure of this protein to be visualized. The protein starts with a signal peptide, followed by the N-terminal globular domain, six repeats of epidermal growth factor-like sequence, a serine/threonine-rich region, a transmembrane domain and a cytoplasmic domain. High-resolution nuclear magnetic resonance (NMR) spectroscopy was employed to define the exact thrombin-binding region. Residues Y413ILDD417 and D423IDE426 are crucial for binding to thrombin; the two critical amino acids for thrombin binding, Ile414 and Ile424, are brought into spatial proximity by ß-sheet structure. There also exist some residues for co-factor activity, namely Asp349, Glu357, Tyr358, Phe376 and Met388. The complex transcriptional and post-transcriptional control of TM underline its importance in a wide variety of biological systems and pathophysiological processes.