Structural characterization of 14-3-3ζ in complex with the human Son of sevenless homolog 1 (SOS1)

J Struct Biol. 2018 Jun;202(3):210-215. doi: 10.1016/j.jsb.2018.01.011. Epub 2018 Feb 1.

Abstract

The deviant Ras activation machinery is found in approximately 30% of all human cancers. SOS1 is an important protagonist of this pathway that plays a key-role in aberrant cell proliferation and differentiation. Interaction of SOS1 with 14-3-3 proteins modulates SOS1 activity in Ras-MAPK signaling. In the present study, we analyze the 14-3-3/SOS1 protein-protein interaction (PPI) by different biochemical assays and report the high resolution crystal structure of a 13-mer motif of SOS1 bound to 14-3-3ζ. These structural and functional insights are important for the evaluation of this PPI interface for small-molecule stabilization as a new starting point for modulating the Ras-Raf-MAPK pathway.

Keywords: Differential scanning fluorimetry; Fluorescence polarization; Isothermal titration calorimetry; Son of sevenless homolog 1; X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / chemistry*
  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / ultrastructure
  • Cell Proliferation / genetics
  • Humans
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / ultrastructure
  • Mutation
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Maps / genetics
  • SOS1 Protein / chemistry*
  • SOS1 Protein / genetics
  • SOS1 Protein / ultrastructure

Substances

  • 14-3-3 Proteins
  • Multiprotein Complexes
  • SOS1 Protein