Structural basis for the NAD-dependent deacetylase mechanism of Sir2

Jeong Ho Chang, Hyun Chul Kim, Kwang Yeon Hwang, Joon Won Lee, Stephen P. Jackson, Stephen D. Bell, Yunje Cho

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)34489-34498
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number37
DOIs
Publication statusPublished - 2002 Sep 13
Externally publishedYes

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Catalysis
NAD
Archaeoglobus fulgidus
Crystal structure
Histone Deacetylases
Gene Silencing
Life Expectancy
Reaction products
DNA Repair
Histones
DNA Damage
Catalytic Domain
Cell Cycle
Repair
Genes
Cells
Derivatives
DNA
Substrates
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Chang, J. H., Kim, H. C., Hwang, K. Y., Lee, J. W., Jackson, S. P., Bell, S. D., & Cho, Y. (2002). Structural basis for the NAD-dependent deacetylase mechanism of Sir2. Journal of Biological Chemistry, 277(37), 34489-34498. https://doi.org/10.1074/jbc.M205460200

Structural basis for the NAD-dependent deacetylase mechanism of Sir2. / Chang, Jeong Ho; Kim, Hyun Chul; Hwang, Kwang Yeon; Lee, Joon Won; Jackson, Stephen P.; Bell, Stephen D.; Cho, Yunje.

In: Journal of Biological Chemistry, Vol. 277, No. 37, 13.09.2002, p. 34489-34498.

Research output: Contribution to journalArticle

Chang, JH, Kim, HC, Hwang, KY, Lee, JW, Jackson, SP, Bell, SD & Cho, Y 2002, 'Structural basis for the NAD-dependent deacetylase mechanism of Sir2', Journal of Biological Chemistry, vol. 277, no. 37, pp. 34489-34498. https://doi.org/10.1074/jbc.M205460200
Chang, Jeong Ho ; Kim, Hyun Chul ; Hwang, Kwang Yeon ; Lee, Joon Won ; Jackson, Stephen P. ; Bell, Stephen D. ; Cho, Yunje. / Structural basis for the NAD-dependent deacetylase mechanism of Sir2. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 37. pp. 34489-34498.
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