Structural Basis for Ca2+-induced Activation for Human PAD4

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  • ARITA Kyouhei
    Field of Supramolecular Biology, International Graduate School of Arts and Sciene, Yokohama City University
  • SATO Mamoru
    Field of Supramolecular Biology, International Graduate School of Arts and Sciene, Yokohama City University

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Other Title
  • カルシウム結合によって活性化されるヒストン修飾酵素ＰＡＤ４の構造科学的基盤
  • サイキン ノ ケンキュウ カラ カルシウム ケツゴウ ニ ヨッテ カッセイカ サレル ヒストン シュウショク コウソ PAD4 ノ コウゾウ カガクテキ キバン

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Abstract

Peptidylarginine deimianse 4 (PAD4) is a Ca2+-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 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 adopts 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 RA.

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