Sir2 proteins are NAD+-dependent protein deacetylases that play key roles in transcriptional regulation, DNA repair, and life span regulation. The structure of an archaeal Sir2 enzyme, Sir2-Af2, bound to an acetylated p53 peptide reveals that the substrate binds in a cleft in the enzyme, forming an enzyme-substrate β sheet with two flanking strands in Sir2-Af2. The acetyl-lysine inserts into a conserved hydrophobic tunnel that contains the active site histidine. Comparison with other structures of Sir2 enzymes suggests that the apoenzyme undergoes a conformational change upon substrate binding. Based on the Sir2-Af2 substrate complex structure, mutations were made in the other A. fulgidus sirtuin, Sir2-Af1, that increased its affinity for the p53 peptide.
Copyright © 2002 Cell Press.
Molecular Cell, Vol 10, 523-535, September 2002
Article
Structure of a Sir2 Enzyme Bound to an Acetylated p53 Peptide
1Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205 USA
2Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205 USA
3Department of Oncology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205 USA
4Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205 USA
Corresponding author
Cynthia Wolberger
410-955-0728 (phone)
410-614-8648 (fax)
cwolberg@jhmi.edu
Summary
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