DEP-domain-mediated regulation of GPCR signaling responses

Cell. 2006 Sep 22;126(6):1079-93. doi: 10.1016/j.cell.2006.07.030.


G protein-coupled receptors (GPCRs) mediate cellular responses to a variety of stimuli, but how specific responses are regulated has been elusive, as the types of GPCRs vastly outnumber the classes of G protein heterotrimers available to initiate downstream signaling. In our analysis of signaling proteins containing DEP domains ( approximately 90 residue sequence motifs first recognized in fly Dishevelled, worm EGL-10, and mammalian Pleckstrin), we find that DEP domains are responsible for specific recognition of GPCRs. We examined the yeast regulator of G protein signaling (RGS) protein Sst2 and demonstrate that the DEP domains in Sst2 mediate binding to its cognate GPCR (Ste2). DEP-domain-mediated tethering promotes downregulation by placing the RGS protein in proximity to its substrate (receptor-activated Galpha subunit). Sst2 docks to the Ste2 cytosolic tail, but only its unphosphorylated state, allowing for release and recycling of this regulator upon receptor desensitization and internalization. DEP-domain-mediated targeting of effectors and regulators to specific GPCRs provides a means to dictate the nature, duration, and specificity of the response.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Cytosol / metabolism
  • Down-Regulation / physiology
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Models, Biological
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding / physiology
  • Protein Structure, Tertiary / physiology
  • Protein Subunits / metabolism
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Mating Factor / genetics
  • Receptors, Mating Factor / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sequence Homology, Amino Acid
  • Signal Transduction / physiology*


  • GTPase-Activating Proteins
  • Protein Subunits
  • Receptors, G-Protein-Coupled
  • Receptors, Mating Factor
  • SST2 protein, S cerevisiae
  • STE2 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins