Mechanistic and structural studies of KDM-catalysed demethylation of histone 1 isotype 4 at lysine 26.pdf (2.08 MB)
Mechanistic and structural studies of KDM-catalysed demethylation of histone 1 isotype 4 at lysine 26.
journal contributionposted on 2019-09-24, 12:56 authored by LJ Walport, RJ Hopkinson, R Chowdhury, Y Zhang, J Bonnici, R Schiller, A Kawamura, CJ Schofield
N-Methylation of lysyl residues is widely observed on histone proteins. Using isolated enzymes, we report mechanistic and structural studies on histone lysine demethylase (KDM)-catalysed demethylation of Nε -methylated lysine 26 on histone 1 isotype 4 (H1.4). The results reveal that methylated H1.4K26 is a substrate for all members of the KDM4 subfamily and that KDM4A-catalysed demethylation of H1.4K26me3 peptide is similarly efficient to that of H3K9me3. Crystallographic studies of an H1.4K26me3:KDM4A complex reveal a conserved binding geometry to that of H3K9me3. In the light of the high activity of the KDM4s on this mark, our results suggest JmjC KDM-catalysed demethylation of H1.4K26 may be as prevalent as demethylation on the H3 tail and warrants further investigation in cells.
This work was supported by grants from Cancer Research UK (C8717/A18245), the Wellcome Trust (091857/7/10/7) and the Biotechnology and Biological Sciences Research Council. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 657292 to LJW. RJH acknowledges a William R. Miller Junior Research Fellowship, St. Edmund Hall. AK acknowledges a Royal Society Dorothy Hodgkin Fellowship (DH120028), ERC Starting Grant (679479) and the Engineering and Physical Science Research Council (EP/L003376/1). JB acknowledges a studentship from the Engineering and Physical Science Research Council (EP/M508111/1). We thank Tristan Smart for purification of KDM2A, the Structural Genomics Consortium for providing KDM5C protein, Sarah Madden for KDM4A protein and Eidarus Salah for KDM4B and KDM4D protein.
CitationFEBS Letters, 2018, 592 (19), pp. 3264-3273
Author affiliation/Organisation/COLLEGE OF SCIENCE AND ENGINEERING/Department of Chemistry
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