Recombinant Human Thrombomodulin (THBD), partial

Function

Endothelial cell receptor that plays a critical role in regulating several physiological processes including hemostasis, coagulation, fibrinolysis, inflammation, and angiogenesis (PubMed:10761923). Acts as a cofactor for thrombin activation of protein C/PROC on the surface of vascular endothelial cells leading to initiation of the activated protein C anticoagulant pathway (PubMed:29323190, PubMed:33836597, PubMed:9395524). Also accelerates the activation of the plasma carboxypeptidase B2/CPB2, which catalyzes removal of C-terminal basic amino acids from its substrates including kinins or anaphylatoxins leading to fibrinolysis inhibition (PubMed:26663133). Plays critical protective roles in changing the cleavage specificity of protease-activated receptor 1/PAR1, inhibiting endothelial cell permeability and inflammation (By similarity). Suppresses inflammation distinctly from its anticoagulant cofactor activity by sequestering HMGB1 thereby preventing it from engaging cellular receptors such as RAGE and contributing to the inflammatory response (PubMed:15841214)

Subcellular Location

Membrane (Single-pass type I membrane protein)

Disease Association

Thrombophilia due to thrombomodulin defect (THPH12) : A hemostatic disorder characterized by a tendency to thrombosis. [The disease may be caused by variants affecting the gene represented in this entry. The role of thrombomodulin in thrombosis is controversial. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis] | Hemolytic uremic syndrome, atypical, 6 (AHUS6) : An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. [Disease susceptibility is associated with variants affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype]

Tissue Specificity

Endothelial cells are unique in synthesizing thrombomodulin

Subunit

Interacts with ITGAL, ITGAM and ITGB2. Interacts with thrombin/F2; this interaction switches the specificity of thrombin from a procoagulant to an anticoagulant and antifibrinolytic protease (PubMed:10761923). Interacts with ANGP1 and ANGP2; these interactions significantly inhibit the generation of activated PC and TAFIa/CPB2 by the thrombin/thrombomodulin complex (PubMed:29323190). Interacts with PF4; this interaction enhances generation of activated protein C (PubMed:9395524). Interacts with HMGB1; this interaction inhibits HMGB1 inflammatory activity (PubMed:15841214)

• Suzuki K. et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. — EMBO J. (1987)
• Wen D. et al. Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene. — Biochemistry (1987)
• Jackman R.W. et al. Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control. — Proc. Natl. Acad. Sci. U.S.A. (1987)
• Shirai T. et al. Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C. — J. Biochem. (1988)
• PubMed: CI-C651T9EDV5RB8 (MAR-)
• Deloukas P. et al. The DNA sequence and comparative analysis of human chromosome 20. — Nature (2001)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Gerlitz B. et al. Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine 474. — Biochem. J. (1993)