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J Biol Chem. 2014 Jun 27;289(26):18302-13. doi: 10.1074/jbc.M114.555052. Epub 2014 May 5.

Human UTY(KDM6C) is a male-specific Nϵ-methyl lysyl demethylase.

Author information

1
From the Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom.
2
the Structural Genomics Consortium, University of Oxford, Headington OX3 7DQ, United Kingdom, and.
3
the Structural Genomics Consortium, University of Oxford, Headington OX3 7DQ, United Kingdom, and the Botnar Research Centre, Oxford Biomedical Research Unit, Oxford OX3 7LD, United Kingdom.
4
From the Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom, christopher.schofield@chem.ox.ac.uk.
5
the Structural Genomics Consortium, University of Oxford, Headington OX3 7DQ, United Kingdom, and catrine.johansson@sgc.ox.ac.uk.

Abstract

The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate- and Fe(II)-dependent oxygenases. KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members that catalyze demethylation of N(ϵ)-methylated histone 3 lysine 27 (H3K27), a mark important for transcriptional repression. Despite reports stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing MS and NMR, that UTY(KDM6C) is an active KDM. Crystallographic analyses reveal that the UTY(KDM6C) active site is highly conserved with those of KDM6B and KDM6A. UTY(KDM6C) catalyzes demethylation of H3K27 peptides in vitro, analogously to KDM6B and KDM6A, but with reduced activity, due to point substitutions involved in substrate binding. The results expand the set of human KDMs and will be of use in developing selective KDM inhibitors.

KEYWORDS:

Chromatin; Dioxygenase; Epigenetics; Histone; Histone Methylation

PMID:
24798337
PMCID:
PMC4140284
DOI:
10.1074/jbc.M114.555052
[Indexed for MEDLINE]
Free PMC Article

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