Structural insights into the π-π-π stacking mechanism and DNA-binding activity of the YEATS domain

Nat Commun. 2018 Nov 1;9(1):4574. doi: 10.1038/s41467-018-07072-6.

Abstract

The YEATS domain has been identified as a reader of histone acylation and more recently emerged as a promising anti-cancer therapeutic target. Here, we detail the structural mechanisms for π-π-π stacking involving the YEATS domains of yeast Taf14 and human AF9 and acylated histone H3 peptides and explore DNA-binding activities of these domains. Taf14-YEATS selects for crotonyllysine, forming π stacking with both the crotonyl amide and the alkene moiety, whereas AF9-YEATS exhibits comparable affinities to saturated and unsaturated acyllysines, engaging them through π stacking with the acyl amide. Importantly, AF9-YEATS is capable of binding to DNA, whereas Taf14-YEATS is not. Using a structure-guided approach, we engineered a mutant of Taf14-YEATS that engages crotonyllysine through the aromatic-aliphatic-aromatic π stacking and shows high selectivity for the crotonyl H3K9 modification. Our findings shed light on the molecular principles underlying recognition of acyllysine marks and reveal a previously unidentified DNA-binding activity of AF9-YEATS.

Publication types

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

MeSH terms

  • Acetylation
  • Acylation
  • Crystallography, X-Ray
  • DNA / metabolism*
  • DNA / ultrastructure
  • Histone Code*
  • Humans
  • Lysine / metabolism
  • Mutation
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / ultrastructure
  • Protein Binding
  • Protein Domains*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Saccharomyces cerevisiae Proteins / ultrastructure
  • Transcription Factor TFIID / chemistry
  • Transcription Factor TFIID / genetics
  • Transcription Factor TFIID / metabolism*
  • Transcription Factor TFIID / ultrastructure

Substances

  • MLLT3 protein, human
  • Nuclear Proteins
  • Saccharomyces cerevisiae Proteins
  • TAF14 protein, S cerevisiae
  • Transcription Factor TFIID
  • DNA
  • Lysine