PADI4-Cit - Precision bifunctional peptide tools to understand protein citrullination
Lead Research Organisation:
Imperial College London
Department Name: Chemistry
Abstract
Protein citrullination is a posttranslational modification (PTM) involved in a wide range of biological functions including epigenetic
gene regulation and the innate immune response. Its dysregulation is implicated in the progress of diverse pathogeneses. Despite
these important roles, our understanding of citrullination remains in its infancy. Citrullination in mammals is catalysed by five
promiscuous isozymes from the peptidylarginine deiminase (PADI) family, which display overlapping substrate specificities and a
range 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 the
effects of citrullination on protein function and gene expression with a level of precision and specificity not currently possible. I will
focus on PADI4, the primarily nuclear member of the PADIs, producing methods to precisely understand the biochemical effects of
single citrullination events in a cell-based context at the substrate level. My new bifunctional tools will be used to address two related
goals: understanding the effect of citrullination on 1) individual protein substrates, and 2) gene regulation. Results from this work
should shed light on this relatively poorly understood PTM, providing new insight into the effects of citrullination on protein function
and a blueprint for future applications to study other substrates and PADIs, with the potential to provide new avenues for therapeutic
intervention.
gene regulation and the innate immune response. Its dysregulation is implicated in the progress of diverse pathogeneses. Despite
these important roles, our understanding of citrullination remains in its infancy. Citrullination in mammals is catalysed by five
promiscuous isozymes from the peptidylarginine deiminase (PADI) family, which display overlapping substrate specificities and a
range 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 the
effects of citrullination on protein function and gene expression with a level of precision and specificity not currently possible. I will
focus on PADI4, the primarily nuclear member of the PADIs, producing methods to precisely understand the biochemical effects of
single citrullination events in a cell-based context at the substrate level. My new bifunctional tools will be used to address two related
goals: understanding the effect of citrullination on 1) individual protein substrates, and 2) gene regulation. Results from this work
should shed light on this relatively poorly understood PTM, providing new insight into the effects of citrullination on protein function
and a blueprint for future applications to study other substrates and PADIs, with the potential to provide new avenues for therapeutic
intervention.
