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J. Biol. Chem., Vol. 277, Issue 37, 34489-34498, September 13, 2002
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From the National Creative Research Initiative Center for
Structural Biology and Department of Life Science, Pohang
University of Science and Technology, Hyo-ja dong, San31, Pohang,
KyungBook 790-784, South Korea, The NAD-dependent histone/protein
deacetylase activity of Sir2 (silent information regulator 2) accounts
for its diverse biological roles including gene silencing, DNA damage
repair, cell cycle regulation, and life span extension. We provide
crystallographic evidence that 2'-O-acetyl ADP-ribose is
the reaction product that is formed at the active site of Sir2 from the
2.6-Å co-crystal structure of 2'-O-acetyl-ADP-ribose and
Sir2 from Archaeoglobus fulgidus. In addition, we show that
His-116 and Phe-159 play critical roles in the catalysis and substrate
recognition. The conserved Ser-24 and Asp-101 contribute to the
stability for NAD binding rather than being directly involved in the
catalysis. The crystal structures of wild type and mutant derivatives
of Sir2, in conjunction with biochemical analyses of the mutants,
provide novel insights into the reaction mechanism of Sir2-mediated deacetylation.
The atomic coordinates and the structure factors (code 1M2G, 1M2H, 1M2J, 1M2K, and 1M2N) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
Structural Basis for the NAD-dependent
Deacetylase Mechanism of Sir2*
, Wellcome
Trust/Cancer Research United Kingdom Institute of Cancer and
Developmental Biology, Tennis Court Rd., Cambridge, CB2 1QR, United
Kingdom, and § Medical Research Council Cancer Cell Unit,
Hills Rd., Cambridge, CB2 2XZ, United Kingdom
*
This work was supported by National Creative Research
Initiatives program, Frontier 21 program, and a KAST young scientist award in life science (to Y. C.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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