UCSF

This thesis focuses on the signaling and trafficking functions of beta-arrestins, which are flexible regulators and transducers for the large G protein-coupled receptor (GPCR) family. The introductory chapter will briefly cover GPCR biology, how the β-arrestins were discovered, the findings that led the canonical understanding of β-arrestin signaling and trafficking functions, recent structural and biophysical advances, as well as the approaches used to obtain the data presented in this thesis. The second chapter describes a new cellular mechanism for β-arrestin function termed ‘catalytic activation’ in which β-arrestins can transiently bind to and be activated by GPCRs. The third chapter provides evidence that lipid engagement by β-arrestins is a key regulator of β-arrestin conformation and function. The fourth chapter will discuss new approaches to understanding the conformational states of β-arrestins and how they may explain the functional flexibility of β-arrestins. The fifth chapter describes a new mechanism of β-arrestin–mediated trafficking and provides a framework for understanding how β-arrestins transduce receptor-specific functions. The final chapter summarizes the major advances from the previous chapters, discusses how these fit with the established findings, and suggests future directions.