Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 11, Issue 8, Pages 777-783Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb799
Keywords
-
Ask authors/readers for more resources
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 alpha/beta 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available