Human UTY(KDM6C) Is a Male-specific Nϵ-Methyl Lysyl Demethylase
| Autor: | M. Vollmar, Sarah K. Madden, Catrine Johansson, Carina Gileadi, Louise J. Walport, Christopher J. Schofield, Udo Oppermann, Richard J. Hopkinson |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Models Molecular Dioxygenase Molecular Sequence Data Lysine urologic and male genital diseases Crystallography X-Ray complex mixtures Methylation Biochemistry Histones Minor Histocompatibility Antigens Species Specificity Histone methylation Humans Amino Acid Sequence Molecular Biology Demethylation biology Nuclear Proteins Active site Cell Biology bacterial infections and mycoses female genital diseases and pregnancy complications Chromatin Protein Structure Tertiary 3. Good health Histone Enzymology biology.protein bacteria Demethylase Epigenetics Histone Methylation Sequence Alignment |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Background: UTY(KDM6C) has been reported previously to be inactive as a histone demethylase. Results: Crystallography reveals that the fold of the UTY(KDM6C) catalytic domain is highly conserved with those of KDM6A/B. UTY(KDM6C) catalyzes demethylation of Nϵ-methylated lysine histone peptides at Lys27. Conclusion: UTY(KDM6C) is a lysine demethylase that shows high structural similarity with KDM6A/B. Significance: UTY(KDM6C) is a functional Nϵ-methyl lysine demethylase. 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 Nϵ-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. |
| Databáze: | OpenAIRE |
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