Methyl-Lysine Recognition by Ankyrin-Repeat Proteins

The ankyrin repeats (ANKs) of the methyltransferases G9a and GLP bind methyllysine (meK) in a surface aromatic cage. Binding the methylation product with the very same polypeptide that generates it seems essential for some G9a/GLP functions, but it is dispensable for others. We first consider the structure of ANKs, particularly to illustrate that different binding modes can exist on the same scaffold and to facilitate the search for other meK-binding ANKs. Huntingtin (HTT)-interacting protein-14 (HIP14) was predicted based on conservation of key cage residues to also have a surface aromatic cage. This prediction has been confirmed, but the HIP14-binding partner remains elusive. HIP14 interacts with HTT through its ANKs. HTT directly binds a methyltransferase and manifests improper patterns of post-translational modification in Huntington’s disease. We have extended the search for other ANKs with meK-binding potential, and we present our results.