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Nat Commun. 2019 Jan 9;10(1):94. doi: 10.1038/s41467-018-07829-z.

Histone H3 binding to the PHD1 domain of histone demethylase KDM5A enables active site remodeling.

Author information

1
Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, Genentech Hall, San Francisco, CA, 94158, USA.
2
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
3
Department of Pharmaceutical Chemistry, University of California, 600 16th Street, Genentech Hall, San Francisco, CA, 94158, USA.
4
Chemistry and Chemical Biology Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, CA, 94158, USA.
5
TETRAD Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, CA, 94158, USA.
6
Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, Genentech Hall, San Francisco, CA, 94158, USA. Danica.Fujimori@ucsf.edu.
7
Department of Pharmaceutical Chemistry, University of California, 600 16th Street, Genentech Hall, San Francisco, CA, 94158, USA. Danica.Fujimori@ucsf.edu.

Abstract

Histone demethylase KDM5A removes methyl marks from lysine 4 of histone H3 and is often overexpressed in cancer. The in vitro demethylase activity of KDM5A is allosterically enhanced by binding of its product, unmodified H3 peptides, to its PHD1 reader domain. However, the molecular basis of this allosteric enhancement is unclear. Here we show that saturation of the PHD1 domain by the H3 N-terminal tail peptides stabilizes binding of the substrate to the catalytic domain and improves the catalytic efficiency of demethylation. When present in saturating concentrations, differently modified H3 N-terminal tail peptides have a similar effect on demethylation. However, they vary greatly in their affinity towards the PHD1 domain, suggesting that H3 modifications can tune KDM5A activity. Furthermore, hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) experiments reveal conformational changes in the allosterically enhanced state. Our findings may enable future development of anti-cancer therapies targeting regions involved in allosteric regulation.

PMID:
30626866
PMCID:
PMC6327041
DOI:
10.1038/s41467-018-07829-z
[Indexed for MEDLINE]
Free PMC Article

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