Signaling at the endosome: cryo-EM structure of a GPCR-G protein-beta-arrestin megacomplex

G protein-coupled receptors (GPCRs) are a large class of cell-surface receptor involved in cellular signaling that are currently the target of over one third of all clinically approved therapeutics. Classically, an agonist-bound, active GPCR couples to and activates G proteins through the receptor intracellular core. To attenuate G protein signaling, the GPCR is phosphorylated at its C-terminal tail and/or relevant intracellular loops, allowing for the recruitment of beta-arrestins (beta arrs). beta arrs then couple to the receptor intracellular core in order to mediate receptor desensitization and internalization. However, our laboratory and others have observed that some GPCRs are capable of continuously signaling through G protein even after internalization. This mode of sustained signaling stands in contrast with our previous understanding of GPCR signaling, and its molecular mechanism is still not well understood. Recently, we have solved the structure of a GPCR-G protein-beta arr megacomplex by cryo-electron microscopy. This 'megaplex' structure illustrates the independent and simultaneous coupling of a G protein to the receptor intracellular core, and binding of a beta arr to a phosphorylated receptor C-terminal tail, with all three components maintaining their respective canonically active conformations. The structure provides evidence for the ability of a GPCR to activate G protein even while being bound to and internalized by beta arr. It also reveals that the binding of G protein and beta arr to the same GPCR is not mutually exclusive, and raises a number of future questions to be answered regarding the mechanism of sustained signaling.

Automated summary

G protein-coupled receptors (GPCRs) are a major class of cell-surface receptors involved in cellular signaling, traditionally thought to signal through G proteins or β-arrestin. However, recent studies have shown that some receptors are capable of sustained signaling even after internalization, challenging previous understanding. This new mechanism of sustained signaling presents new research directions and challenges.