Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9

Peter R. Nielsen, Daniel Nietlispach, Helen R. Mott, Juliana Callaghan, Andrew Bannister, Tony Kouzarides, Alexey G. Murzin, Natalia V. Murzina () and Ernest D. Laue ()
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Peter R. Nielsen: University of Cambridge
Daniel Nietlispach: University of Cambridge
Helen R. Mott: University of Cambridge
Juliana Callaghan: University of Cambridge
Andrew Bannister: University of Cambridge
Tony Kouzarides: University of Cambridge
Alexey G. Murzin: MRC Centre for Protein Engineering
Natalia V. Murzina: University of Cambridge
Ernest D. Laue: University of Cambridge

Nature, 2002, vol. 416, issue 6876, 103-107

Abstract: Abstract Specific modifications to histones are essential epigenetic markers1—heritable changes in gene expression that do not affect the DNA sequence. Methylation of lysine 9 in histone H3 is recognized by heterochromatin protein 1 (HP1), which directs the binding of other proteins to control chromatin structure and gene expression2,3,4. Here we show that HP1 uses an induced-fit mechanism for recognition of this modification, as revealed by the structure of its chromodomain bound to a histone H3 peptide dimethylated at Nζ of lysine 9. The binding pocket for the N-methyl groups is provided by three aromatic side chains, Tyr 21, Trp 42 and Phe 45, which reside in two regions that become ordered on binding of the peptide. The side chain of Lys 9 is almost fully extended and surrounded by residues that are conserved in many other chromodomains. The QTAR peptide sequence preceding Lys 9 makes most of the additional interactions with the chromodomain, with HP1 residues Val 23, Leu 40, Trp 42, Leu 58 and Cys 60 appearing to be a major determinant of specificity by binding the key buried Ala 7. These findings predict which other chromodomains will bind methylated proteins and suggest a motif that they recognize.

Date: 2002
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DOI: 10.1038/nature722

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