BioScience Trends. 2022;16(6):444-446. (DOI: 10.5582/bst.2022.01472)

Thrombin cleaves recombinant soluble thrombomodulin into a lectin-like domain fragment and a fragment with protein C-activating cofactor activity

Yokoyama H, Tateishi K, Baba Y, Kobayashi A, Hashimoto M, Fukuda S, Yamao H, Maruyama T, Nakata M, Matsushita M

Thrombomodulin (TM) is a transmembrane protein that plays an important role in regulating the coagulation system by acting as a cofactor for thrombin in protein C activation. Additionally, TM is involved in inflammation. Previous studies have shown that soluble fragments of TM of varying sizes, which are derived from membrane-bound TM, are present in plasma and urine. Soluble fragments of TM are speculated to exhibit biological activity. Among these, a lectin-like domain fragment (TMD1) is of particular importance. Recombinant TMD1 has previously been shown to attenuate lipopolysaccharide-induced inflammation. Here, we report that thrombin cleaves recombinant soluble TM, which is used for the treatment of disseminated intravascular coagulation associated with sepsis, into TMD1 and a fragment comprising the C-terminal portion of TM (TMD23), the latter of which retains the cofactor activity for activating protein C. Our findings suggest that thrombin not only activates protein C on membrane-bound TM but may also cleave TM to generate TMD1.

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