Structural Basis of Arrestin-Dependent Signal Transduction. Issue 6 (June 2018)

• Record Type: Journal Article
• Authors: Chen, Qiuyan; Iverson, Tina M.; Gurevich, Vsevolod V.
• Is Part Of: Trends in biochemical sciences. Volume 43:Issue 6(2018)
• Page Start: 412
• Page End: 423
• Publication Date: 2018-06
• Subjects: arrestin -- structure -- activation -- GPCR -- cell signaling; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2018.03.005
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Arrestins are a small family of proteins with four isoforms in humans. Remarkably, two arrestins regulate signaling from >800 G protein-coupled receptors (GPCRs) or nonreceptor activators by simultaneously binding an activator and one out of hundreds of other signaling proteins. When arrestins are bound to GPCRs or other activators, the affinity for these signaling partners changes. Thus, it is proposed that an activator alters arrestin's ability to transduce a signal. The comparison of all available arrestin structures identifies several common conformational rearrangements associated with activation. In particular, it identifies elements that are directly involved in binding to GPCRs or other activators, elements that likely engage distinct downstream effectors, and elements that likely link the activator-binding sites with the effector-binding sites. Highlights: Free arrestins have very similar conformations in crystal structures, with the relative orientation of the two domains held by several intramolecular interactions. These interactions are destabilized by activators: active phosphorylated GPCRs and inositol hexakisphosphate (IP6 ), an inositol metabolite abundant in the cytoplasm. The latest high-resolution structure of the nonvisual arrestin-3 with IP6 suggests molecular mechanisms of arrestin activation that induce characteristic rearrangements in the arrestin molecule. Arrestin-1, -2, and -3, activated by different means, demonstrate a global conformational rearrangement. In particular, several elements of activated arrestins dramatically change their conformation from basal to active, which is very similar in all arrestin subtypes. These elements (that we propose to call 'arrestin switches', by analogy with G protein switch regions) are likely docking sites for the signaling and trafficking proteins that preferentially bind active arrestins. As arrestins bind numerous protein partners, narrowing the search of their docking sites to arrestin switch regions will greatly facilitate the identification of the elements and individual residues specific for each interaction. Identification of the binding sites of nonreceptor signaling proteins paves the way for the design of signaling-biased arrestins, where particular capabilities are specifically disabled or enhanced. This would be a novel, potent tool for targeted manipulation of cell signaling for research and therapy.