title: Autodeimination of protein arginine deiminase 4 alters protein-protein interactions but not activity.
abstract: The protein arginine deiminases (PAD), which catalyze the hydrolysis of peptidyl-arginine to form peptidyl-citrulline, play important roles in a variety of cell signaling pathways, including apoptosis, differentiation, and transcriptional regulation. In addition to these important cellular roles, PAD activity is dysregulated in multiple human diseases [e.g., rheumatoid arthritis (RA), cancer, and colitis], and significantly, PAD inhibition with Cl-amidine has been shown to reduce disease severity in the collagen-induced arthritis model of RA. Although these enzymes play important roles in human cell signaling and disease, the mechanisms that regulate PAD activity under both physiological and pathological conditions are poorly understood. One possible mechanism for regulating PAD activity is autodeimination, to which PAD4 has been shown by us and others to be subjected in vitro and in vivo. Herein, we demonstrate that PAD4 autodeimination does not alter the activity, substrate specificity, or calcium dependence of this isozyme. However, the results of these studies indicate a novel role for autodeimination in modulating the ability of PAD4 to interact with histone deacetylase 1 (HDAC1), citrullinated histone H3 (Cit H3), and protein arginine methyltransferase 1 (PRMT1).
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Slack
authors.forename: Larry E
authors.initials: LE
authors.lastname: Jones
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bhatia
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
mesh_terms: D004789:Enzyme Activation / Q000235:genetics; D018922:HL-60 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007097:Imines / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D007097:Imines; D011994:Recombinant Proteins; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D006867:Hydrolases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases