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

DEP-domain-mediated regulation of GPCR signaling responses

Daniel R Ballon  1 , Paul L Flanary, Douglas P Gladue, James B Konopka, Henrik G Dohlman, Jeremy Thorner
Affiliations
Free article

DEP-domain-mediated regulation of GPCR signaling responses

Daniel R Ballon et al. Cell. .
Free article

Abstract

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.

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