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Studies on the catalytic domains of multiple JmjC oxygenases using peptide substrates

DOI: 10.4161/15592294.2014.983381 DOI Help
PMID: 25625844 PMID Help

Authors: Sophie T Williams (Chemistry Research Laboratory; Oxford) , Louise J Walport (Chemistry Research Laboratory; Oxford) , Richard J Hopkinson (Chemistry Research Laboratory; Oxford) , Sarah K Madden (Chemistry Research Laboratory; Oxford) , Rasheduzzaman Chowdhury (Chemistry Research Laboratory; Oxford) , Christopher J Schofield (Chemistry Research Laboratory; Oxford) , Akane Kawamura (Chemistry Research Laboratory; Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Epigenetics , VOL 9 (12) , PAGES 1596 - 1603

State: Published (Approved)
Published: January 2015

Abstract: The JmjC-domain-containing 2-oxoglutarate-dependent oxygenases catalyze protein hydroxylation and Nemethyllysine demethylation via hydroxylation. A subgroup of this family, the JmjC lysine demethylases (JmjC KDMs) are involved in histone modifications at multiple sites. There are conflicting reports as to the substrate selectivity of some JmjC oxygenases with respect to KDM activities. In this study, a panel of modified histone H3 peptides was tested for demethylation against 15 human JmjC-domain-containing proteins. The results largely confirmed known Nemethyllysine substrates. However, the purified KDM4 catalytic domains showed greater substrate promiscuity than previously reported (i.e., KDM4A was observed to catalyze demethylation at H3K27 as well as H3K9/K36). Crystallographic analyses revealed that the Ne-methyllysine of an H3K27me3 peptide binds similarly to Ne-methyllysines of H3K9me3/H3K36me3 with KDM4A. A subgroup of JmjC proteins known to catalyze hydroxylation did not display demethylation activity. Overall, the results reveal that the catalytic domains of the KDM4 enzymes may be less selective than previously identified. They also draw a distinction between the Ne-methyllysine demethylation and hydroxylation activities within the JmjC subfamily. These resultswill be of use to thoseworkingon functional studies of the JmjCenzymes.

Journal Keywords: Demethylation; Epigenetics; Histone; Methyllysine; Jmjc Histone Demethylase; 2Og Oxygenases

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography