Phosphorylation of an Intrinsically Disordered Segment in Ets1 Shifts Conformational Sampling toward Binding-Competent Substates

• Published in: Structure (London) 2014-08, Vol.22 (8), p.1196-1203
• Main Authors: Bui, Jennifer M., Gsponer, Jörg
• Format: Article
• Language: English
• Subjects: Binding; Compatibility; Humans; Hydrophobic and Hydrophilic Interactions; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - metabolism; Mathematical analysis; Models, Molecular; Molecular Dynamics Simulation; Peptide Fragments - metabolism; Phosphates; Phosphorylation; Protein Binding; Protein Conformation; Proteins; Proto-Oncogene Protein c-ets-1 - chemistry; Proto-Oncogene Protein c-ets-1 - metabolism; Sampling; Segments; Sialoglycoproteins - metabolism
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2014.06.002

Functions of many proteins are affected by posttranslational modifications of intrinsically disordered (ID) regions, yet little is known about the underlying molecular mechanisms. By combining molecular dynamics simulations and protein docking, we demonstrate that the addition of phosphates to an ID segment adjacent to the PNT domain of Ets1 directs conformational sampling toward substates that are most compatible with high-affinity binding of the TAZ1 domain of its coactivator CBP. The phosphate charges disrupt salt bridges and thereby open a hydrophobic cleft and expose hydrophobic residues at the ID N terminus. The structure of the PNT-TAZ1 complex that we determined shows that PNT binds to TAZ1 via these hydrophobic regions in a similar manner to how it interacts with other partners. Our calculations reveal a dual effect of phosphorylation in that it changes the dynamics of PNT so that it becomes more compatible for TAZ1 binding and increases complementarity with this binding partner. [Display omitted] •Phosphorylation redirects sampling of PNT toward binding-competent substates•Introduced protein docking protocol generates a model of the PNT-TAZ complex•Properties of complex model are consistent with transcriptional assay results•TAZ binds PNT in a manner similar to that in which it binds to disordered partners Combining molecular dynamics simulations, community network analysis, and protein-protein docking reveals how phosphorylation of an intrinsically disordered segment in Ets-1 enhances binding to its coactivator CBP.