4j2q | pdb_00004j2q
Crystal structure of C-terminally truncated arrestin reveals mechanism of arrestin activation
Structural highlights
DiseaseARRS_BOVIN Note=S-antigen induces autoimmune uveitis. FunctionARRS_BOVIN Arrestin is one of the major proteins of the ros (retinal rod outer segments); it binds to photoactivated-phosphorylated rhodopsin, thereby apparently preventing the transducin-mediated activation of phosphodiesterase. Isoform B plays a role in the phototransduction cascade. Publication Abstract from PubMedArrestins interact with G-protein-coupled receptors (GPCRs) to block interaction with G proteins and initiate G-protein-independent signalling. Arrestins have a bi-lobed structure that is stabilized by a long carboxy-terminal tail (C-tail), and displacement of the C-tail by receptor-attached phosphates activates arrestins for binding active GPCRs. Structures of the inactive state of arrestin are available, but it is not known how C-tail displacement activates arrestin for receptor coupling. Here we present a 3.0 A crystal structure of the bovine arrestin-1 splice variant p44, in which the activation step is mimicked by C-tail truncation. The structure of this pre-activated arrestin is profoundly different from the basal state and gives insight into the activation mechanism. p44 displays breakage of the central polar core and other interlobe hydrogen-bond networks, leading to a approximately 21 degrees rotation of the two lobes as compared to basal arrestin-1. Rearrangements in key receptor-binding loops in the central crest region include the finger loop, loop 139 (refs 8, 10, 11) and the sequence Asp 296-Asn 305 (or gate loop), here identified as controlling the polar core. We verified the role of these conformational alterations in arrestin activation and receptor binding by site-directed fluorescence spectroscopy. The data indicate a mechanism for arrestin activation in which C-tail displacement releases critical central-crest loops from restricted to extended receptor-interacting conformations. In parallel, increased flexibility between the two lobes facilitates a proper fitting of arrestin to the active receptor surface. Our results provide a snapshot of an arrestin ready to bind the active receptor, and give an insight into the role of naturally occurring truncated arrestins in the visual system. Crystal structure of pre-activated arrestin p44.,Kim YJ, Hofmann KP, Ernst OP, Scheerer P, Choe HW, Sommer ME Nature. 2013 Apr 21. doi: 10.1038/nature12133. PMID:23604253[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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