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Published Online April 6, 2006
Science DOI: 10.1126/science.1125162

Reports

Submitted on January 19, 2006
Accepted on March 27, 2006

Recognition of Histone H3 Lysine-4 Methylation by the Double Tudor Domain of JMJD2A

Ying Huang 1, Jia Fang 2, Mark T. Bedford 3, Yi Zhang 2, Rui-Ming Xu 1*

1 W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Present address: Structural Biology Program, Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
2 Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
3 The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Post Office Box 389, Smithville, TX 78957, USA.

* To whom correspondence should be addressed.
Rui-Ming Xu , E-mail: rmxu{at}saturn.med.nyu.edu

Biological responses to histone methylation critically depend on the faithful readout and transduction of the methyl-lysine signal by "effector" proteins, yet our understanding of methyl-lysine recognition has so far been limited to the study of histone binding by chromodomain and WD40-repeat proteins. The double tudor domain of JMJD2A, a Jmjc domain-containing histone demethylase, binds methylated histone H3-K4 and H4-K20. We found that the double tudor domain has an interdigitated structure and the unusual fold is required for its ability to bind methylated histone tails. The cocrystal structure of the JMJD2A double tudor domain with a trimethylated H3-K4 peptide reveals that the trimethyl-K4 is bound in a cage of three aromatic residues, two of which are from the tudor-2 motif, while the binding specificity is determined by side-chain interactions involving amino acids from the tudor-1 motif. Our study provides mechanistic insights into recognition of methylated histone tails by tudor domains and reveals the structural intricacy of methyl-lysine recognition by two closely spaced effector domains.


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