title: Structural basis for histone and phosphohistone binding by the GCN5 histone acetyltransferase.
abstract: Distinct posttranslational modifications on histones occur in specific patterns to mediate certain chromosomal events. For example, on histone H3, phosphorylation at Ser10 can enhance GCN5-mediated Lys14 acetylation to promote transcription. To gain insight into the mechanism underlying this synergism, we determined the structure of Tetrahymena GCN5 (tGCN5) and coenzyme A (CoA) bound to unmodified and Ser10-phosphorylated 19 residue histone H3 peptides (H3p19 and H3p19Pi, respectively). The tGCN5/CoA/H3p19 structure reveals that a 12 amino acid core sequence mediates extensive contacts with the protein, providing the structural basis for substrate specificity by the GCN5/PCAF family of histone acetyltransferases. Comparison with the tGCN5/CoA/H3p19Pi structure reveals that phospho-Ser10 and Thr11 mediate significant histone-protein interactions, and nucleate additional interactions distal to the phosphorylation site. Functional studies show that histone H3 Thr11 is necessary for optimal transcription at yGcn5-dependent promoters requiring Ser10 phosphorylation. Together, these studies reveal how one histone modification can modulate another to affect distinct transcriptional signals.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Clements
authors.forename: Arienne N
authors.initials: AN
authors.lastname: Poux
authors.forename: Wan-Sheng
authors.initials: WS
authors.lastname: Lo
authors.forename: Lorraine
authors.initials: L
authors.lastname: Pillus
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D051548:Histone Acetyltransferases; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D015719:Single-Strand Specific DNA and RNA Endonucleases / Q000378:metabolism; D013379:Substrate Specificity; D013768:Tetrahymena / Q000378:metabolism; D013912:Threonine / Q000737:chemistry; D014158:Transcription, Genetic; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006657:Histones; D015719:Single-Strand Specific DNA and RNA Endonucleases; D013912:Threonine; C120128:tGCN5 histone acetyltransferase; D000099224:p300-CBP-Associated Factor