Phosphorylation of an intrinsically disordered region of Ets1 shifts a multi-modal interaction ensemble to an auto-inhibitory state

Nucleic Acids Res. 2018 Mar 16;46(5):2243-2251. doi: 10.1093/nar/gkx1297.

Abstract

Multi-modal interactions are frequently observed in intrinsically disordered regions (IDRs) of proteins upon binding to their partners. In many cases, post-translational modifications in IDRs are accompanied by coupled folding and binding. From both molecular simulations and biochemical experiments with mutational studies, we show that the IDR including a Ser rich region (SRR) of the transcription factor Ets1, just before the DNA-binding core domain, undergoes multi-modal interactions when the SRR is not phosphorylated. In the phosphorylated state, the SRR forms a few specific complex structures with the Ets1 core, covering the recognition helix in the core and drastically reducing the DNA binding affinities as the auto-inhibitory state. The binding kinetics of mutated Ets1 indicates that aromatic residues in the SRR can be substituted with other hydrophobic residues for the interactions with the Ets1 core.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Intrinsically Disordered Proteins / chemistry*
  • Intrinsically Disordered Proteins / metabolism
  • Kinetics
  • Molecular Dynamics Simulation*
  • Phosphorylation
  • Protein Binding
  • Protein Folding*
  • Protein Processing, Post-Translational*
  • Proto-Oncogene Protein c-ets-1 / chemistry*
  • Proto-Oncogene Protein c-ets-1 / metabolism
  • Serine / chemistry
  • Serine / genetics
  • Serine / metabolism

Substances

  • Intrinsically Disordered Proteins
  • Proto-Oncogene Protein c-ets-1
  • Serine