Biochemical insights into structure and function of arrestins

Abstract

Arrestins (arr) are multifunctional cytosolic adaptors that bind to active and phosphorylated G protein-coupled receptors (GPCRs) via a highly versatile interface. Arrestins stop G protein signaling and trigger other signaling pathways. Recently, 3D structures of arr–GPCR complexes have been solved, which provide a bulk of structural information for understanding the mechanism of arr recruitment and activation. However, many questions about the functional consequences of structural details and the dynamics of the arr–GPCR interaction remain open. A wealth of information about key determinants for the arr–GPCR interaction and their functional relevance, and dynamic insights into the process of arr binding and the functional outcomes of different binding modes have been provided by a series of biochemical methods which we review here. Importantly, most of these methods provide information from the live cell, which is a necessary validation and complement for structural data. With the main focus on the most recent research, we will highlight major findings about arr structure, function, and dynamics derived from mutagenesis studies, cross-linking studies, conformational probes, and sensors, and we summarize available systems to detect arr recruitment. Furthermore, we discuss recent findings and directions of in silico investigations in arr–GPCR complexes.