Role of PDZ proteins in regulating trafficking, signaling, and function of GPCRs: means, motif, and opportunity

Abstract

PDZ proteins, named for the common structural domain shared by the postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (DlgA), and zonula occludens-1 protein (ZO-1), constitute a family of 200-300 recognized members. These cytoplasmic adapter proteins are capable of assembling a variety of membrane-associated proteins and signaling molecules in short-lived functional units. Here, we review PDZ proteins that participate in the regulation of signaling, trafficking, and function of G protein-coupled receptors. Salient structural features of PDZ proteins that allow them to recognize targeted GPCRs are considered. Scaffolding proteins harboring PDZ domains may contain single or multiple PDZ modules and may also include other protein-protein interaction modules. PDZ proteins may impact receptor signaling by diverse mechanisms that include retaining the receptor at the cell membrane, thereby increasing the duration of ligand binding, as well as importantly influencing GPCR internalization, trafficking, recycling, and intracellular sorting. PDZ proteins are also capable of modifying the assembled complex of accessory proteins such as β-arrestins that themselves regulate GPCR signaling. Additionally, PDZ proteins may modulate GPCR signaling by altering the G protein to which the receptor binds, or affect other regulatory proteins that impact GTPase activity, protein kinase A, phospholipase C, or modify downstream signaling events. Small molecules targeting the PDZ protein-GPCR interaction are being developed and may become important and selective drug candidates.

FIGURE I

Schematic representation of select human PDZ proteins discussed in this review. PDZ and other protein modules are indicated by respective shapes and color. The relative scale is shown on the bottom. Domain name abbreviations: PDZ=PSD-95, Drosophila discs large, and the adherens junction protein, ZO 1; PH=pleckstrin homology; SU=syntrophin unique; L27=Lin2, Lin7-like; SH3=SRC homology 3; GUK=guanylate kinase; PX=phosphoinositide-binding; RAS=RAt Sarcoma; DIX=Disheveled homology; DEP=Disheveled, EGL-10, Pleckstrin; RGSL=regulator of G-protein signaling like; DH=DBL (diffuse B-cell lymphoma) homology.