An Interplay of Structure and Intrinsic Disorder in the Functionality of Peptidylarginine Deiminases, a Family of Key Autoimmunity-related Enzymes

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Calcium-dependent protein, Disorder-based functionality, Eukaryotic linear motif, Inactivation mechanism, Molecular recognition feature, MoRF, PAD activity, PAD inhibitor, Post-translational modification, Protein–protein interaction, PTM, Structural analysis, Structural disorder

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Citrullination is a post-translation modification of proteins, where the proteinaceous arginine residues are converted to non-coded citrulline residues. The immune tolerance to such citrullinated protein can be lost, leading to inflammatory and autoimmune diseases. Citrullination is a chemical reaction mediated by peptidylarginine deiminase enzymes (PADs), which are a family of calcium-dependent cysteine hydrolase enzymes that includes five isotypes: PAD1, PAD2, PAD3, PAD4, and PAD6. Each PAD has specific substrates and tissue distribution, where it modifies the arginine to produce a citrullinated protein with altered structure and function. All mammalian PADs have a sequence similarity of about 70–95%, whereas in humans, they are 50–55% homologous in their structure and amino acid sequences. Being calcium-dependent hydrolases, PADs are inactive under the physiological level of calcium, but could be activated due to distortions in calcium homeostasis, or when the cellular calcium levels are increased. In this article, we analyze some of the currently available data on the structural properties of human PADs, the mechanisms of their calcium-induced activation, and show that these proteins contain functionally important regions of intrinsic disorder. Citrullination represents an important trigger of multiple physiological and pathological processes, and as a result, PADs are recognized to play a number of important roles in autoimmune diseases, cancer, and neurodegeneration. Therefore, we also review the current state of the art in the development of PAD inhibitors with good potency and selectivity.

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Cellular and Molecular Life Sciences, v. 76, p. 4635-4662