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

James E. Longbotham, Cynthia M. Chio, Venkatasubramanian Dharmarajan, Michael J. Trnka, Idelisse Ortiz Torres, Devrishi Goswami, Karen Ruiz, Alma L. Burlingame, Patrick R. Griffin and Danica Galonić Fujimori ()
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James E. Longbotham: University of California
Cynthia M. Chio: University of California
Venkatasubramanian Dharmarajan: The Scripps Research Institute
Michael J. Trnka: University of California
Idelisse Ortiz Torres: University of California
Devrishi Goswami: The Scripps Research Institute
Karen Ruiz: University of California
Alma L. Burlingame: University of California
Patrick R. Griffin: The Scripps Research Institute
Danica Galonić Fujimori: University of California

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07829-z

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