Molecular Model for the C-type Lectin Domain of Human Thrombomodulin

Thrombomodulin (TM) is a multi-modular membrane receptor (557 residues) present on the surface of endothelial cells. TM binds thrombin (T) and this complex promotes downregulation of the coagulation cascade via activation of protein C and delay fibrinolysis through activation of the thrombin-activatable fibrinolysis inhibitor (TAFI). The N-term region (155 residues) of TM possesses the signature of the C-type lectin domain. This module seems required for constitutive internalization of the T-TM complex, plays a role in the modulation of cell growth and may direct soluble forms of TM (or T-TM) to specific regions of the vasculature during inflammation and in a variety of vascular disorders. The understanding of this domain is however limited and structural information would contribute to the design of new experiments aiming at characterizing its functions. We have developed a 3D model for the lectin domain of TM using prediction-based threading and comparative model building. The X-ray structures of lithostathine (LIT), mannose-binding protein (MBP) and E-selectin (ESL) were used as initial templates. Despite a sequence identity of about 28 % between TM and LIT (best score) it is possible to build an accurate 3D model for TM. The TM lectin domain contains two α-helices, two β-sheets and a compact hydrophobic/aromatic core. The disulfide bridging pattern of TM has not been reported experimentally but the model proposes the formation of four disulfide bonds between C12-C17, C34-C149, C78-C115 and C119-C140. Based on the model, potential binding sites are proposed.