Peptidyl arginine deiminases are implicated in a wide range of patho(physiological) processes including the innate immune response, skin homeostasis and early embryonic development. Much of this activity is attributed to catalytic citrullination of arginine residues in diverse substrate proteins including histone proteins, filaggrin and myelin basic protein. Despite their wide-ranging biological roles, the mechanisms through which PADIs are regulated within cells remain poorly understood. Combining cyclic peptide tool development with biochemical and structural approaches we have been exploring the mechanisms of PADI activation. In this talk I will present two stories of recent work from our lab: Firstly, I will present our work to develop cyclic peptide activators of PADI4. Our lead peptide activates citrullination both in vitro and in cells.
CryoEM studies reveal that activation occurs through binding to the allosteric hinge region of PADI4, providing support for a similar regulatory mechanism in cells by which PADI4 could be activated by allosteric protein binding partners. Secondly, I will present recent structural work from our lab exploring the non-catalytic role of PADI6 in early embryonic development, shedding light on the elusive final member of the PADI family, PADI6.