Arrestins and protein ubiquitination.

The adaptor proteins, β-arrestins 1 and 2, were originally identified as inhibitors of G protein signaling at the seven-transmembrane receptors (7TMRs, also called G protein-coupled receptors or GPCRs). Subsequent studies have established β-arrestins as critical multifunctional 7TMR adaptors that mediate receptor trafficking and activate G protein-independent signaling pathways. 7TMR activation leads not only to the recruitment of arrestin proteins upon phosphorylation by GPCR kinases but also to β-arrestin ubiquitination. This posttranslational modification of β-arrestin is appended by specific E3 ubiquitin ligases and reversed by deubiquitinases, which are also recruited in a receptor- and agonist-specific manner. β-Arrestin ubiquitination allows it to form protein complexes with activated 7TMRs, endocytic proteins such as clathrin, and phosphorylated ERK1/2. β-Arrestin ubiquitination is dependent on its activated conformation and likely regulates timing and subcellular localization of various protein interactions during receptor trafficking and signaling. β-Arrestins also serve as adaptors that escort E3 ubiquitin ligases to mediate ubiquitination of a wide list of substrate proteins including 7TMRs and provide an added layer of regulation for defining substrate specificity in the cellular ubiquitination pathway.

Duke Scholars

Author Sudha Kaup Shenoy Medicine, Cardiology