Structure of a Sir2 enzyme bound to an acetylated p53 peptide

Jose L. Avalos; Ivana Celic; Shabazz Muhammad; Michael S. Cosgrove; Jef D. Boeke; Cynthia Wolberger

doi:10.1016/S1097-2765(02)00628-7

Structure of a Sir2 enzyme bound to an acetylated p53 peptide

Jose L. Avalos, Ivana Celic, Shabazz Muhammad, Michael S. Cosgrove, Jef D. Boeke, Cynthia Wolberger

Research output: Contribution to journal › Article › peer-review

223 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	523-535
Number of pages	13
Journal	Molecular Cell
Volume	10
Issue number	3
DOIs	https://doi.org/10.1016/S1097-2765(02)00628-7
State	Published - Sep 1 2002

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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title = "Structure of a Sir2 enzyme bound to an acetylated p53 peptide",

abstract = "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.",

author = "Avalos, \{Jose L.\} and Ivana Celic and Shabazz Muhammad and Cosgrove, \{Michael S.\} and Boeke, \{Jef D.\} and Cynthia Wolberger",

note = "Funding Information: We thank R.M. Xu for providing the coordinates of the Sir2-Af1 complex in its closed conformation and S. Berger for the CBP expression plasmid. We thank L. Berman and M. Becker for their help at beamline X25 of the National Synchrotron Light Source at Brookhaven National Laboratory, R. Campbell for his advice and help in the structure determination, and P. Cole, M. Amzel, M. Bianchet, M. Faig, A. Mildvan, A. VanDemark, and C. Garvie for helpful discussions. This work was supported by grant GM62385 (J.D.B. and C.W.) from the National Institutes of Health and by National Research Service Award CA84760-02 (M.S.C.) from the National Cancer Institute. ",

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T1 - Structure of a Sir2 enzyme bound to an acetylated p53 peptide

AU - Avalos, Jose L.

AU - Celic, Ivana

AU - Muhammad, Shabazz

AU - Cosgrove, Michael S.

AU - Boeke, Jef D.

AU - Wolberger, Cynthia

N1 - Funding Information: We thank R.M. Xu for providing the coordinates of the Sir2-Af1 complex in its closed conformation and S. Berger for the CBP expression plasmid. We thank L. Berman and M. Becker for their help at beamline X25 of the National Synchrotron Light Source at Brookhaven National Laboratory, R. Campbell for his advice and help in the structure determination, and P. Cole, M. Amzel, M. Bianchet, M. Faig, A. Mildvan, A. VanDemark, and C. Garvie for helpful discussions. This work was supported by grant GM62385 (J.D.B. and C.W.) from the National Institutes of Health and by National Research Service Award CA84760-02 (M.S.C.) from the National Cancer Institute.

PY - 2002/9/1

Y1 - 2002/9/1

N2 - 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.

AB - 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.

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Structure of a Sir2 enzyme bound to an acetylated p53 peptide

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