The Role of Protein Citrullination in Pathological Thrombosis

11:00 a.m.

Zoom

Ronak Tilvawala (Assistant Professor,  Department of Molecular Biosciences, University of Kansas)

Thrombosis is the formation of blood clots inside the blood vessel, which obstructs the blood from flowing naturally through the circulatory system. More than 2 million people die each year of thrombosis or its consequences in the United States. Despite this, the mechanism of pathological thrombosis remains poorly understood. Recent studies suggest that protein citrullination—a post-translational modification (PTM) of arginine-- plays a role in thrombus formation. Notably, the coagulation cascade is regulated by arginine-specific serine proteases. How protein citrullinated alters the regulation of arginine-specific serine proteases during thrombosis yet remains unknown, mainly because of the technical challenges of identifying low abundance PTMs from a complex biological system.  Besides, citrullination changes the mass of protein by only 0.98 Da, making it even more difficult to study. Our lab is pioneering in developing innovative proteomic techniques to study this tiny but essential PTM.

        We have developed a novel chemoproteomic approach to identify citrullinated proteins directly from patient samples. Using our approach, we identified more than 150 novel citrullinated proteins from rheumatoid arthritis patient samples. Amongst the known citrullinated proteins, serine protease inhibitors (SERPINs) and serine proteases that regulate coagulation and fibrinolysis were highly citrullinated in our dataset. We further showed that citrullination inactivates P1-Arg containing SERPINs against their cognate proteases. Besides, our studies demonstrate that the citrullination of P1-Arg containing SERPINs alters their activity under physiological conditions. Overall, these data enhance our understanding of how SERPIN citrullination controls the activity of coagulation cascade proteases and provide new directions to study the regulation of serine protease signaling in health and diseases.