Abstract
Methylation is one of the important post-translational modifications that play critical roles in regulating protein functions. Proteomic identification of this post-translational modification and understanding how it affects protein activity remain great challenges. We tackled this problem from the aspect of methylation mediating protein-protein interaction. Using the chromodomain of human chromobox protein homolog 6 as a model system, we developed a systematic approach that integrates structure modeling, bioinformatics analysis, and peptide microarray experiments to identify lysine residues that are methylated and recognized by the chromodomain in the human proteome. Given the important role of chromobox protein homolog 6 as a reader of histone modifications, it was interesting to find that the majority of its interacting partners identified via this approach function in chromatin remodeling and transcriptional regulation. Our study not only illustrates a novel angle for identifying methyllysines on a proteome-wide scale and elucidating their potential roles in regulating protein function, but also suggests possible strategies for engineering the chromodomain-peptide interface to enhance the recognition of and manipulate the signal transduction mediated by such interactions.
Highlights
Post-translational modification (PTM)1 is essential for the proper biological function of many proteins in almost every organism
It was first identified in Drosophila melanogaster as a heterochromatin-associated protein and a component of polycomb repressive complex 1 (PRC1), which is related to gene repression [20]
We present here a systematic approach that integrates structural modeling, bioinformatics analysis, and peptide microarray binding assay to identify methyllysine-containing peptides in the human proteome that may bind to the chromobox protein homolog 6 (CBX6) chromodomain
Summary
Post-translational modification (PTM) is essential for the proper biological function of many proteins in almost every organism. Biochemistry and proteomics studies have identified a series of PTMs [1], including phosphorylation [2], glycosylation [3], acetylation [4, 5], ubiquitinoylation [6], sumoylation [7, 8], and methylation (9 –11) These PTMs relate to a wide range of important biological processes and functions, From the ‡Department of Chemistry and Biochemistry, 9500 Gilman Drive, University of California, San Diego, La Jolla, California 92093-0359; ¶Department of Cellular and Molecular Medicine, 9500 Gilman Drive, University of California, San Diego, La Jolla, California 92093-0359. Polycomb protein comprises a family of histone modification readers that recognize methylated H3K9/ H3K27 [18, 19] It was first identified in Drosophila melanogaster as a heterochromatin-associated protein and a component of polycomb repressive complex 1 (PRC1), which is related to gene repression [20]. Levy et al discovered 118 proteins that can be methylated by lysine
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