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J. Biol. Chem., Vol. 283, Issue 28, 19626-19635, July 11, 2008

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Specificity of the Chromodomain Y Chromosome Family of Chromodomains for Lysine-methylated ARK(S/T) Motifs^*

Wolfgang Fischle, A Robert Black fellow of the Damon Runyon Cancer Research Foundation^¶12, Henriette Franz^¶1, Steven A. Jacobs³, C. David Allis, and Sepideh Khorasanizadeh⁴

From the Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, Virginia 22908-0733, Laboratory of Chromatin Biology, The Rockefeller University, New York, New York 10021, and ^¶Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany

Previous studies have shown two homologous chromodomain modules in the HP1 and Polycomb proteins exhibit discriminatory binding to related methyllysine residues (embedded in ARKS motifs) of the histone H3 tail. Methylated ARK(S/T) motifs have recently been identified in other chromatin factors (e.g. linker histone H1.4 and lysine methyltransferase G9a). These are thought to function as peripheral docking sites for the HP1 chromodomain. In vertebrates, HP1-like chromodomains are also present in the chromodomain Y chromosome (CDY) family of proteins adjacent to a putative catalytic motif. The human genome encodes three CDY family proteins, CDY, CDYL, and CDYL2. These have putative functions ranging from establishment of histone H4 acetylation during spermiogenesis to regulation of transcription co-repressor complexes. To delineate the biochemical functions of the CDY family chromodomains, we analyzed their specificity of methyllysine recognition. We detected substantial differences among these factors. The CDY chromodomain exhibits discriminatory binding to lysine-methylated ARK(S/T) motifs, whereas the CDYL2 chromodomain binds with comparable strength to multiple ARK(S/T) motifs. Interestingly, subtle amino acid changes in the CDYL chromodomain prohibit such binding interactions in vitro and in vivo. However, point mutations can rescue binding. In support of the in vitro binding properties of the chromodomains, the full-length CDY family proteins exhibit substantial variability in chromatin localization. Our studies underscore the significance of subtle sequence differences in a conserved signaling module for diverse epigenetic regulatory pathways.

Received for publication, April 4, 2008 , and in revised form, April 29, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM064786 (to S. K.), GM63959, and GM53512 (to C. D. A.). This work was also supported by the Max Planck Society (to W. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ These authors contributed equally to this work.

³ Present address: Centocor Research & Development, Radnor, PA, 19087.

² To whom correspondence may be addressed. E-mail: wfischl{at}gwdg.de. ⁴ To whom correspondence may be addressed. E-mail: khorasan{at}virginia.edu.

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