New Insights into GPCR–Transducer Coupling

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2018

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Abstract

β-arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, initiate signaling on their own, and mediate receptor endocytosis.  Using a panel of GPCRs believed to couple differently to βarrs we demonstrate how distinct conformations of GPCR–βarr complexes are specialized to perform different subsets of these cellular functions. Our results thus provide a new signaling paradigm for the understanding of GPCRs, whereby a specific GPCR–βarr conformation mediates receptor desensitization, while another drives internalization and some forms of signaling.

In addition, some GPCRs activate G proteins from within internalized cellular compartments resulting in sustained signaling. We used a variety of biochemical, biophysical, and cell-based methods to demonstrate the existence, functionality, and architecture of internalized receptor “mega-complexes” composed of a single GPCR, βarr, and G protein. EM of purified ‘megaplexes’ reveals that a single receptor binds simultaneously through its core region with G protein and with βarr in the tail conformation. Thus, the two GPCR–βarr conformations carry out distinct cellular functions.

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Cahill, Thomas J. (2018). New Insights into GPCR–Transducer Coupling. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/16774.

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