Catalytic activation of β-arrestin by GPCRs

Abstract

β-arrestins are critical regulator and transducer proteins for G protein-coupled receptors (GPCRs). Cellular β-arrestin function is presently thought to require stable and stoichiometric GPCR/β-arrestin scaffold complex formation driven by the phosphorylated GPCR tail. We demonstrate a distinct and additional mechanism that does not require stable GPCR/β-arrestin scaffolding or the GPCR tail. Instead, it is activated by transient engagement of the GPCR core that destabilizes a conserved inter-domain charge network in β-arrestin. This promotes capture of β-arrestin at the plasma membrane and accumulation in clathrin-coated endocytic structures (CCSs) after GPCR dissociation, requiring a series of β-arrestin interactions with membrane phosphoinositides and CCS lattice proteins. β-arrestin clustering in CCSs without its upstream activating GPCR is associated with a β-arrestin-dependent component of the cellular ERK (Extracellular signal-regulated kinase) response. These results delineate a discrete mechanism of cellular β-arrestin function that is activated catalytically by GPCRs.

GPCR signaling: conformational activation of arrestins

“…The findings by Latoracca et al obtained primarily by computational approaches, are consistent with those of Eichel et al, 5 who, using a variety of cell biological techniques, also demonstrate that transient interactions of the GPCR transmembrane core are sufficient to activate β-arrestin. Eichel and colleagues had previously shown that, after dissociating from the β 1 -adrenergic receptor (β 1 AR), β-arrestin-2 remains in its active state and can transduce β-arrestin-mediated ERK1/2 signaling from clathrincoated structures (CCSs).…”

“…However, the two new papers illuminate the distinct roles of both the R P -tail and the 7 TM core in mediating arrestin interaction with and activation by GPCRs. 4,5 Specifically, these studies focus a much brighter light on the mechanisms of arrestin activation by the GPCR core. Using atomic-level molecular dynamic simulations of arrestin and β-arrestin, Latorraca and colleagues investigated the structural mechanisms by which the R P -tail, and the transmembrane core, in particular, regulate arrestin activation.…”

“…4,5 Protein members of the versatile arrestin family contain two major domains (N and C), which consist largely of β-sheets and connecting loops. While initially discovered in the context of receptor desensitization, it was subsequently discovered that β-arrestins also serve as multifunctional adapters mediating receptor interaction with several components of the clathrincoated pit endocytic machinery, thus mediating receptor internalization and trafficking.…”

“…Such activation of β-arrestin in the plasma membrane involves a series of interactions with membrane phosphoinositides, accumulation in CCSs, and subsequent MAP kinase signaling activity in the absence of the activating receptor. 5 Activation of β-arrestin via transient engagement with the GPCR core requires the disruption of a conserved inter-domain interaction network within β-arrestin. 5 This network is located proximal to the finger loop, which is known to play a role in maintaining β-arrestin in its inactive state.…”

“…5 Activation of β-arrestin via transient engagement with the GPCR core requires the disruption of a conserved inter-domain interaction network within β-arrestin. 5 This network is located proximal to the finger loop, which is known to play a role in maintaining β-arrestin in its inactive state.…”