Structural basis for histone and phosphohistone binding by the GCN5 histone acetyltransferase.
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.
Clements
Adrienne
A
The Wistar Institute, Philadelphia, PA 19104, USA.
Poux
Arienne N
AN
Lo
Wan-Sheng
WS
Pillus
Lorraine
L
Berger
Shelley L
SL
Marmorstein
Ronen
R
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
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