Peptidyl arginine deiminase 4 (PAD4) is an enzyme expressed in neutrophils that, when activated, can drive the formation of neutrophil extracellular traps (NETs). Uncontrolled activation of PAD4 and subsequent citrullination of proteins is increasingly recognized as a driver of (auto) immune diseases. Currently, our understanding of PAD4 structure-function relationships and activity control in vivo is incomplete. In this review, employed molecular modelling to generate a three-dimensional structure of the complete PAD4 molecule. Using our model we discuss the catalytic conversion of the arginine substrate to citrulline. Besides mechanistic insight into PAD4 function, we give an overview of biological functions of PAD4 and mechanisms that influence its activation. In addition we discuss the crucial role of PAD4 mediated citrullination of histones in the formation of neutrophil extracellular traps(NET). Subsequently we focus on the role of PAD4 mediated NET formation and its role in pathogenesis of rheumatoid arthritis, sepsis and (immune-)thrombosis. Finally, we summarize current efforts to design different classes of PAD4 inhibitors that are being developed for improved treatment of autoimmune disorders as well as thrombo-inflammatory disease.
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