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J Biol Chem. 2014 Jul 25;289(30):20991-1002. doi: 10.1074/jbc.M114.560680. Epub 2014 May 27.

Identification of receptor binding-induced conformational changes in non-visual arrestins.

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From the Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and.
the Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
From the Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and


The non-visual arrestins, arrestin-2 and arrestin-3, belong to a small family of multifunctional cytosolic proteins. Non-visual arrestins interact with hundreds of G protein-coupled receptors (GPCRs) and regulate GPCR desensitization by binding active phosphorylated GPCRs and uncoupling them from heterotrimeric G proteins. Recently, non-visual arrestins have been shown to mediate G protein-independent signaling by serving as adaptors and scaffolds that assemble multiprotein complexes. By recruiting various partners, including trafficking and signaling proteins, directly to GPCRs, non-visual arrestins connect activated receptors to diverse signaling pathways. To investigate arrestin-mediated signaling, a structural understanding of arrestin activation and interaction with GPCRs is essential. Here we identified global and local conformational changes in the non-visual arrestins upon binding to the model GPCR rhodopsin. To detect conformational changes, pairs of spin labels were introduced into arrestin-2 and arrestin-3, and the interspin distances in the absence and presence of the receptor were measured by double electron electron resonance spectroscopy. Our data indicate that both non-visual arrestins undergo several conformational changes similar to arrestin-1, including the finger loop moving toward the predicted location of the receptor in the complex as well as the C-tail release upon receptor binding. The arrestin-2 results also suggest that there is no clam shell-like closure of the N- and C-domains and that the loop containing residue 136 (homolog of 139 in arrestin-1) has high flexibility in both free and receptor-bound states.


Arrestin; Electron Paramagnetic Resonance (EPR); G Protein-coupled Receptor (GPCR); Rhodopsin; Spectroscopy

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