Structural basis for histone and phosphohistone binding by the GCN5 histone acetyltransferase

Mol Cell. 2003 Aug;12(2):461-73. doi: 10.1016/s1097-2765(03)00288-0.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylation
  • Acetyltransferases / chemistry*
  • Acetyltransferases / metabolism
  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Histone Acetyltransferases
  • Histones / genetics
  • Histones / metabolism*
  • Kinetics
  • Models, Biological
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Secondary
  • Single-Strand Specific DNA and RNA Endonucleases / metabolism
  • Substrate Specificity
  • Tetrahymena / metabolism
  • Threonine / chemistry
  • Transcription, Genetic


  • Histones
  • Threonine
  • Acetyltransferases
  • Histone Acetyltransferases
  • tGCN5 histone acetyltransferase
  • Single-Strand Specific DNA and RNA Endonucleases

Associated data

  • PDB/1PU9
  • PDB/1PUA