Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain

Structure. 2016 Sep 6;24(9):1606-12. doi: 10.1016/j.str.2016.05.023. Epub 2016 Aug 18.

Abstract

Histone lysine acylations play an important role in the regulation of gene transcription in chromatin. Unlike histone acetyl-lysine, molecular recognition of a recently identified crotonyl-lysine mark is much less understood. Here, we report that the YEATS domain of AF9 preferentially binds crotonyl-lysine over acetyl-lysine in histone H3. Nuclear magnetic resonance structural analysis reveals that crotonyl-lysine of histone H3 lysine 18 is engulfed deep in an aromatic cage of the YEATS domain where the carbonyl oxygen of crotonyl-lysine forms a hydrogen bond with the backbone amide of protein residue Tyr78. The crotonyl-lysine, through its unique electron-rich double-bond side chain, engages π-π aromatic stacking and extended hydrophobic/aromatic interactions with the YEATS domain compared with acetyl-lysine. Our mutational analysis confirmed key protein residues Phe59 and Tyr78 for crotonyl-lysine recognition. Importantly, our findings present a new structural mechanism of protein-protein interactions mediated by histone lysine crotonylation, and show how the cells interpret acyl-lysine marks in different biological contexts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Histones / chemistry*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Lysine / analogs & derivatives*
  • Lysine / chemistry
  • Lysine / metabolism
  • Models, Molecular
  • Mutation
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phenylalanine / chemistry
  • Phenylalanine / metabolism
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Tyrosine / chemistry
  • Tyrosine / metabolism

Substances

  • Histones
  • MLLT3 protein, human
  • Nuclear Proteins
  • Recombinant Proteins
  • epsilon-N-crotonyllysine
  • N(alpha)-acetyllysine
  • Tyrosine
  • Phenylalanine
  • Lysine