Post-translational modifications (PTMs) play critical roles in regulating protein functions and mediating protein-protein interaction. An important PTM is lysine methylation that orchestrates chromatin modifications and regulates functions of non-histone proteins. Methyllysine peptides are bound by modular domains, of which chromodomains are representative. Here, we conducted the first comprehensive study of all chromodomains in the human proteome interacting with both histone and non-histone methyllysine peptides. We observed significant degenerate binding between chromodomains and histone peptides, i.e. different histone sites can be recognized by the same set of chromodomains, and different chromodomains can share similar binding profiles to individual histone sites. Such degenerate binding is not dictated by amino acid sequence or PTM motif but rather rooted in the physiochemical properties defined by the PTMs on the histone peptides. This molecular mechanism is confirmed by the accurate prediction of the binding specificity using a computational model that captures the structural and energetic patterns of the domain-peptide interaction. Furthermore, guided by the computational model, we completed the first targeted engineering of the chromodomain binding profiles towards hundreds of peptides by mutating only three residues on the interaction interface. This study presents a systematic approach to deciphering the domain-peptide recognition and pinpointing the critical residues of which mutation could manipulate this recognition.

Deciphering and engineering chromodomain-methyllysine peptide recognition

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.