<h3>Title</h3>
<h3><span style="font-size: 12.16px;">Chemical Biology of Protein Citrullination</span></h3>
<p><strong><span style="font-size: 12.16px;"><span style="text-decoration: underline;">Abstract</span> :</span></strong></p>
<p><span style="font-size: 12.16px;">In this seminar, I’ll discuss my postdoctoral research on protein citrullination, a post-translational modification associated with multiple autoimmune disorders, and my research proposals.</span></p>
<p><span style="font-size: 12.16px;">Protein citrullination by protein arginine deiminases (PADs – PAD1, 2, 3 and 4) plays pivotal roles in several physiological processes, such as epigenetic regulation of gene expression, neutrophil extracellular trap (NET) formation and DNA-damage induced apoptosis. However, aberrant protein citrullination by PADs is associated with multiple autoimmune disorders, including rheumatoid arthritis (RA), multiple sclerosis (MS), ulcerative colitis (UC) and lupus, neurodegenerative diseases and certain forms of cancer. For example, a citrulline-specific probe, Biotin-PG and chemoproteomics platform enabled us to identify various classes of novel citrullinated proteins, including serine protease inhibitors (SERPINs), serine proteases, transport proteins and complement system components along with known citrullinated proteins (e.g., vimentin, enolase, keratin and fibrin) in the serum, synovial fluid and synovial tissue of RA patients. Although the list of citrullinated proteins is ever expanding, the effect of citrullination on the structure and activity of a given protein remains poorly understood mainly due to the lack of a method for site-specific incorporation of citrulline into proteins. We developed a novel technology that enables the site-specific incorporation of citrulline (Cit) into proteins in mammalian cells. This approach exploits an engineered E. coli-derived leucyl tRNA synthetase-tRNA pair that incorporates a photocaged-citrulline (SM60) into proteins in response to a nonsense codon. Subsequently, SM60 is readily converted to Cit with light in vitro and in living cells. To demonstrate the utility of the method, we biochemically characterized the effect of incorporating Cit at two known autocitrullination sites in Protein Arginine Deiminase 4 (PAD4, R372 and R374) and showed that the R372Cit and R374Cit mutants are 181- and 9-fold less active than the wild-type enzyme.</span></p>
<p><span style="font-size: 12.16px;">Additionally, I’ll discuss my future plans for research on the covalent modification and degradation of proteins, and photochemical control of the bioactivity of small molecules.</span></p>
<p><span style="font-size: 12.16px;">References:</span></p>
<p><span style="font-size: 12.16px;">1. S. Mondal, P. R. Thompson, Acc. Chem. Res. 2019, 52, 818.</span></p>
<p><span style="font-size: 12.16px;">2. S. Mondal, S. Wang, Y. Zheng, S. Sen, A. Chatterjee, P. R. Thompson, Nat. Commun.</span></p>
<p><span style="font-size: 12.16px;">2020, Manuscript Accepted.</span></p>
<p> </p>
<p><span style="font-size: 12.16px;">(Preprint: bioRxiv, https://doi.org/10.1101/2020.06.06.137885)</span></p>
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