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 beta 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.
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Avalos
authors.forename: Ivana
authors.initials: I
authors.lastname: Celic
authors.forename: Shabazz
authors.initials: S
authors.lastname: Muhammad
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cosgrove
authors.forename: Jef D
authors.initials: JD
authors.lastname: Boeke
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wolberger
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D019843:Archaeal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019611:Archaeoglobus fulgidus / Q000201:enzymology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D037761:Sirtuins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019843:Archaeal Proteins; D010455:Peptides; D016159:Tumor Suppressor Protein p53; D037761:Sirtuins