title: Phosphorylation of an intrinsically disordered segment in Ets1 shifts conformational sampling toward binding-competent substates.
abstract: 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.
authors.affiliation: The Qualcomm Institute, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-4040, USA. Electronic address: jennbui@eng.ucsd.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bui
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada. Electronic address: gsponer@chibi.ubc.ca.
authors.forename: Jörg
authors.initials: J
authors.lastname: Gsponer
mesh_terms: D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D050784:Proto-Oncogene Protein c-ets-1 / Q000737:chemistry* / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism
chemical_list: C494041:ETS1 protein, human; D064267:Intrinsically Disordered Proteins; D010446:Peptide Fragments; D050784:Proto-Oncogene Protein c-ets-1; D012795:Sialoglycoproteins; C571744:bone sialoprotein (35-62), human