Peptidylarginine deimianse 4 (PAD4) is a Ca
2+-dependent enzyme that catalyzes the conversion of both arginine and mono-methyl arginine in histones into citrullines, and regulates both histone argininine methylation level and gene activity. Its gene is susceptibility locus for rheumatoid arthritis (RA) . Here we present the crystal structure of Ca
2+-free wild-type PAD4, which shows that the polypeptide chain adopts an elongated fold in which the N-terminal domain forms two immunoglobulin-like subdomains, and the C-terminal domain forms an α/β propeller structure. Five Ca
2+-binding sites, none of which adopts an EF-hand motif, were identified in the structure of a Ca
2+-bound inactive mutant with and without bound substrate. These structural data indicate that Ca
2+binding induces conformational changes that generate the active site cleft. Our findings identify a novel mechanism for enzyme activation by Ca
2+ions, and are important for understanding the mechanism of protein citrullination and for developing PAD-inhibiting drugs for the treatment of RA.
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