2. Academic Validation
  3. Structural insights into the π-π-π stacking mechanism and DNA-binding activity of the YEATS domain

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.
Brianna J Klein 1,  Kendra R Vann 1,  Forest H Andrews 1,  Wesley W Wang 2,  Jibo Zhang 3,  Yi Zhang 1,  Anastasia A Beloglazkina 4,  Wenyi Mi 5,  Yuanyuan Li 6,  Haitao Li 6,  Xiaobing Shi 5,  Andrei G Kutateladze 4,  Brian D Strahl 3,  Wenshe R Liu 2,  Tatiana G Kutateladze 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
  • 2 Department of Chemistry, Texas A&M University, College Station, TX, 77843, USA.
  • 3 Department of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
  • 4 Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA.
  • 5 Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
  • 6 Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, P.R. China.
  • 7 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA. tatiana.kutateladze@ucdenver.edu.
PMID: 30385749 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.

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