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Crystal structure and functional analysis of JMJD5 indicate an alternate specificity and function
Paul A Del Rizzo1, Swathi Krishnan, Raymond C Trievel
1Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
Molecular and Cellular Biology
|August 2, 2012
Summary
JMJD5, also known as KDM8, does not demethylate histone H3K36me2 as previously thought. Structural and biochemical data suggest JMJD5 may function as a protein hydroxylase, independent of histone demethylation roles.
Area of Science:
- Biochemistry
- Structural Biology
- Epigenetics
Background:
- JMJD5 (KDM8) is a Jumonji C (JmjC) protein linked to various biological processes, including cancer and development.
- Previous studies suggested JMJD5 functions as a histone demethylase, specifically targeting H3K36me2 to regulate cell cycle genes.
Purpose of the Study:
- To elucidate the structural and biochemical properties of the JMJD5 catalytic domain.
- To investigate the enzymatic activity of JMJD5, particularly its role in histone demethylation.
Main Methods:
- High-resolution crystal structure determination of the human JMJD5 catalytic domain.
- Biochemical assays to assess demethylase activity on various histone methylation marks.
Main Results:
- Crystal structures revealed a conserved JmjC β-barrel fold with a distinct active site cleft.
- JMJD5 shares structural homology with hydroxylases like FIH-1 and JMJD6, but limited homology with lysine demethylases (KDMs).
- Biochemical assays demonstrated no detectable demethylase activity of JMJD5 on H3K36me2 or other histone methyllysines.
Conclusions:
- Contrary to prior reports, JMJD5 does not exhibit histone demethylase activity.
- The structural and biochemical data suggest JMJD5 may function as a protein hydroxylase, playing roles beyond histone modification.
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