DEP-Domain-Mediated Regulation of GPCR Signaling Responses

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.

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

“…S2). Of note, the yeast Sst2 DEP domain was previously shown to bind the GPCR family member Ste2, which is distantly related to Fz receptors, suggesting involvement of a highly conserved binding mode (46).…”

Comparative genomics of MAP kinase and calcium–calcineurin signalling components in plant and human pathogenic fungi

“…S. pombe Sst2 is significantly shorter (480 aa) than the rest of the orthologues (650-780 aa). All Sst2 proteins share the RGS domain, but the predicted A. gossypii and C. albicans proteins lack a conserved DEP-like segment (residues 50-135) which is required for binding to the cognate G protein-coupled receptor Ste2 (Ballon et al, 2006).…”

DEP Domain Containing 1 is a Novel Diagnostic Marker and Prognostic Predictor for Hepatocellular Carcinoma

“…DEP domain is a globular domain that consists of approximately 90 amino acids, which was first identified in three proteins: D. melanogaster Dishevelled, C. elegans EGL-10 and mammalian Pleckstrin (Ballon et al, 2006). These proteins are involved in Wnt signaling (Sokol, 2000), G-protein coupled receptor signaling , and signaling in platelets and neutrophils (Kharrat et al, 1998), respectively.…”