The complement system is a major component of innate immunity and its activation depends on component C3. Complement component C3 is a multidomain protein which can be activated to C3b via any of three activation pathways as the third step in a proteolytic cascade. Once active, C3b continues the activation cascade which eventually leads to creation of a membrane attack complex (MAC) that is able to lyse bacteria and damage host cells. When misregulated, MAC can also attack healthy cells. Due to the complex nature of the activation of the complement system, the more intricate molecular details have not yet been elucidated, but several regulators are known. One of these regulators is thrombomodulin (TM) which is better known for its role in regulating blood clotting. Several in vivo studies have shown that the lectin-like domain of TM interferes with complement activation. Our in vitro work has shown that TM can bind to C3, and we have used hydrogen/deuterium exchange mass spectrometry (HDXMS) and fluorescence assays to begin to understand the effect of TM binding on C3.

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