PADI4-Cit - Precision bifunctional peptide tools to understand protein citrullination

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Protein citrullination is a posttranslational modification (PTM) involved in a wide range of biological functions including epigeneticgene regulation and the innate immune response. Its dysregulation is implicated in the progress of diverse pathogeneses. Despitethese important roles, our understanding of citrullination remains in its infancy. Citrullination in mammals is catalysed by fivepromiscuous isozymes from the peptidylarginine deiminase (PADI) family, which display overlapping substrate specificities and arange of tissue expression patterns. This complex landscape makes precise understanding of the effects of citrullination challenging,with no general strategies currently available to explore citrullination at the single substrate level. To dissect this complicated system,I aim to develop bifunctional chemical tools to recruit PADI enzymes to specific substrates and genes, allowing investigation of theeffects of citrullination on protein function and gene expression with a level of precision and specificity not currently possible. I willfocus on PADI4, the primarily nuclear member of the PADIs, producing methods to precisely understand the biochemical effects ofsingle citrullination events in a cell-based context at the substrate level. My new bifunctional tools will be used to address two relatedgoals: understanding the effect of citrullination on 1) individual protein substrates, and 2) gene regulation. Results from this workshould shed light on this relatively poorly understood PTM, providing new insight into the effects of citrullination on protein functionand a blueprint for future applications to study other substrates and PADIs, with the potential to provide new avenues for therapeuticintervention.