Structural basis for Ca2+-induced activation of human PAD4

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Abstract
Peptidylarginine deiminase 4 (PAD4) is a Ca2+-dependent enzyme that catalyzes the conversion of protein arginine residues to citrulline. Its gene is a susceptibility locus for rheumatoid arthritis. Here we present the crystal structure of Ca2+-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 Ca2+-binding sites, none of which adopt an EF-hand motif, were identified in the structure of a Ca2+-bound inactive mutant with and without bound substrate. These structural data indicate that Ca2+ binding induces conformational changes that generate the active site cleft. Our findings identify a novel mechanism for enzyme activation by Ca2+ ions, and are important for understanding the mechanism of protein citrullination and for developing PAD-inhibiting drugs for the treatment of rheumatoid arthritis.