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Nature Structural & Molecular Biology 15, 245–250 (1 March 2008) | doi:10.1038/nsmb.1384

The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules

Robert E Collins , Jeffrey P Northrop , John R Horton , David Y Lee , Xing Zhang , Michael R Stallcup & Xiaodong Cheng

Histone modifications have important roles in transcriptional control, mitosis and heterochromatin formation. G9a and G9a-like protein (GLP) are euchromatin-associated methyltransferases that repress transcription by mono- and dimethylating histone H3 at Lys9 (H3K9). Here we demonstrate that the ankyrin repeat domains of G9a and GLP bind with strong preference to N-terminal H3 peptides containing mono- or dimethyl K9. X-ray crystallography revealed the basis for recognition of the methylated lysine by a partial hydrophobic cage with three tryptophans and one acidic residue. Substitution of key residues in the cage eliminated the H3 tail interaction. Hence, G9a and GLP contain a new type of methyllysine binding module (the ankyrin repeat domains) and are the first examples of protein (histone) methyltransferases harboring in a single polypeptide the activities that generate and read the same epigenetic mark.