Rewiring of RSK-PDZ Interactome by Linear Motif Phosphorylation

J Mol Biol. 2019 Mar 15;431(6):1234-1249. doi: 10.1016/j.jmb.2019.01.038. Epub 2019 Feb 3.

Abstract

Phosphorylation of short linear peptide motifs is a widespread process for the dynamic regulation of protein-protein interactions. However, the global impact of phosphorylation events on the protein-protein interactome is rarely addressed. The disordered C-terminal tail of ribosomal S6 kinase 1 (RSK1) binds to PDZ domain-containing scaffold proteins, and it harbors a phosphorylatable PDZ-binding motif (PBM) responsive to epidermal growth factor stimulation. Here, we examined binding of two versions of the RSK1 PBM, either phosphorylated or unphosphorylated at position -3, to almost all (95%) of the 266 PDZ domains of the human proteome. PBM phosphorylation dramatically altered the PDZ domain-binding landscape of RSK1, by strengthening or weakening numerous interactions to various degrees. The RSK-PDZome interactome analyzed in this study reveals how linear motif-based phospho-switches convey stimulus-dependent changes in the context of related network components.

Keywords: MAPK; PDZ; RSK; phosphorylation; protein–protein interaction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Epidermal Growth Factor / metabolism
  • Humans
  • Models, Molecular
  • PDZ Domains*
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs*
  • Ribosomal Protein S6 Kinases, 90-kDa / chemistry*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • RHOA protein, human
  • Epidermal Growth Factor
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • rhoA GTP-Binding Protein