Structural basis for the 14-3-3 protein-dependent inhibition of the regulator of G protein signaling 3 (RGS3) function

J Biol Chem. 2011 Dec 16;286(50):43527-36. doi: 10.1074/jbc.M111.273573. Epub 2011 Oct 25.


Regulator of G protein signaling (RGS) proteins function as GTPase-activating proteins for the α-subunit of heterotrimeric G proteins. The function of certain RGS proteins is negatively regulated by 14-3-3 proteins, a family of highly conserved regulatory molecules expressed in all eukaryotes. In this study, we provide a structural mechanism for 14-3-3-dependent inhibition of RGS3-Gα interaction. We have used small angle x-ray scattering, hydrogen/deuterium exchange kinetics, and Förster resonance energy transfer measurements to determine the low-resolution solution structure of the 14-3-3ζ·RGS3 complex. The structure shows the RGS domain of RGS3 bound to the 14-3-3ζ dimer in an as-yet-unrecognized manner interacting with less conserved regions on the outer surface of the 14-3-3 dimer outside its central channel. Our results suggest that the 14-3-3 protein binding affects the structure of the Gα interaction portion of RGS3 as well as sterically blocks the interaction between the RGS domain and the Gα subunit of heterotrimeric G proteins.

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 / metabolism*
  • Circular Dichroism
  • Fluorescence Resonance Energy Transfer
  • GTP-Binding Proteins / chemistry*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • GTPase-Activating Proteins / chemistry*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Mass Spectrometry
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RGS Proteins
  • Scattering, Small Angle
  • Signal Transduction


  • 14-3-3 Proteins
  • GTPase-Activating Proteins
  • RGS Proteins
  • RGS3 protein, human
  • GTP-Binding Proteins