Journal
STRUCTURE
Volume 23, Issue 1, Pages 206-215Publisher
CELL PRESS
DOI: 10.1016/j.str.2014.11.004
Keywords
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Funding
- Ontario Ministry of Economic Development Innovation
- Canada Research Chair in Structural Biology and Epigenetics
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Canadian Institutes of Health Research [GMX-209406]
- NSERC
- University of Ottawa
- Canada Foundation for Innovation
- Fonds de Recherche en Sante du Quebec
- Ontario Graduate Scholarship
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Characterization of lysine methylation has proven challenging despite its importance in biological processes such as gene transcription, protein turnover, and cytoskeletal organization. In contrast to other key posttranslational modifications, current proteomics techniques have thus far shown limited success at characterizing methyl-lysine residues across the cellular landscape. To complement current biochemical characterization methods, we developed a multistate computational protein design procedure to probe the substrate specificity of the protein lysine methyltransferase SMYD2. Modeling of substrate-bound SMYD2 identified residues important for substrate recognition and predicted amino acids necessary for methylation. Peptide- and protein- based substrate libraries confirmed that SMYD2 activity is dictated by the motif [LFM](-1)-K*-[AFYMSHRK](+1)- [LYK](+2) around the target lysine K*. Comprehensive motif-based searches and mutational analysis further established four additional substrates of SMYD2. Our methodology paves the way to systematically predict and validate posttranslational modification sites while simultaneously pairing them with their associated enzymes.
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