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

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

Author information

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.

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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