Formation and Decay of the Arrestin·Rhodopsin Complex in Native Disc Membranes

Beyrière, Florent; Sommer, Monika; Szczepek, Michal; Bartl, Franz; Hofmann, Klaus Peter; Heck, M.; Ritter, Eglof

doi:10.1074/jbc.m114.620898

Cited by 13 publications

(5 citation statements)

References 57 publications

(75 reference statements)

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“…This proposed survival mechanism not only precludes G t signaling but also promotes re-uptake of atRAL by rhodopsin, therefore delaying MII decay and regeneration of the dark state, and enhancing atRAL sequestration ( Sommer et al, 2012 ; Sommer and Farrens, 2006 ). Although the other rhodopsin in the homodimer bound by arrestin is likely free to decay to the inactive conformation, permitting regeneration with 11CR ( Sommer et al, 2012 ; Schafer and Farrens, 2015 ; Beyrière et al, 2015 ), a higher intrinsic stability of the active conformation would not only likely delay regeneration with 11CR, but also likely push the equilibrium toward atRAL re-uptake —a process that could be even further promoted if atRAL levels are high ( Sommer et al, 2012 ; Schafer et al, 2016 ), such as within dark-adapted animals exposed to bright flashes ( Saari et al, 1998 ; Lee et al, 2010 , and within disease models where atRAL clearance is delayed ( Maeda et al, 2009 ; Chen et al, 2012c . The evolution of high conformational selectivity of active-state rhodopsin for atRAL—a distinguishing feature from the cone opsinsmay therefore play a key role within these putatively photoprotective ternary complexes, which have been previously proposed to provide an atRAL sink for rods in bright light ( Sommer et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Functional trade-offs and environmental variation shaped ancient trajectories in the evolution of dim-light vision

Castiglione

Chang

2018

eLife

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Trade-offs between protein stability and activity can restrict access to evolutionary trajectories, but widespread epistasis may facilitate indirect routes to adaptation. This may be enhanced by natural environmental variation, but in multicellular organisms this process is poorly understood. We investigated a paradoxical trajectory taken during the evolution of tetrapod dim-light vision, where in the rod visual pigment rhodopsin, E122 was fixed 350 million years ago, a residue associated with increased active-state (MII) stability but greatly diminished rod photosensitivity. Here, we demonstrate that high MII stability could have likely evolved without E122, but instead, selection appears to have entrenched E122 in tetrapods via epistatic interactions with nearby coevolving sites. In fishes by contrast, selection may have exploited these epistatic effects to explore alternative trajectories, but via indirect routes with low MII stability. Our results suggest that within tetrapods, E122 and high MII stability cannot be sacrificed—not even for improvements to rod photosensitivity.

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Section: Discussionmentioning

confidence: 99%

Functional trade-offs and environmental variation shaped ancient trajectories in the evolution of dim-light vision

Castiglione

Chang

2018

eLife

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“…Light induces isomerization of the ligand to the agonist all- trans -retinal, resulting in the active receptor species Metarhodopsin II (Meta II). This experimental system affords the advantage that pre-complex and high-affinity complex interactions can be separately observed 14 15 .…”

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confidence: 99%

C-edge loops of arrestin function as a membrane anchor

et al. 2017

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G-protein-coupled receptors are membrane proteins that are regulated by a small family of arrestin proteins. During formation of the arrestin–receptor complex, arrestin first interacts with the phosphorylated receptor C terminus in a pre-complex, which activates arrestin for tight receptor binding. Currently, little is known about the structure of the pre-complex and its transition to a high-affinity complex. Here we present molecular dynamics simulations and site-directed fluorescence experiments on arrestin-1 interactions with rhodopsin, showing that loops within the C-edge of arrestin function as a membrane anchor. Activation of arrestin by receptor-attached phosphates is necessary for C-edge engagement of the membrane, and we show that these interactions are distinct in the pre-complex and high-affinity complex in regard to their conformation and orientation. Our results expand current knowledge of C-edge structure and further illuminate the conformational transitions that occur in arrestin along the pathway to tight receptor binding.

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“…Such changes interfere with identifying receptor changes when monitored by FTIR spectroscopy, making unambiguous band assignments challenging (30). Therefore, to allow more straightforward and unambiguous interpretation of our data, we made use of ArrFL-1, a synthetic peptide derived from the finger loop of arrestin-1 (rod visual arrestin, 67 YGQEDIDVMGL 77 ) (31).…”

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confidence: 99%

The arrestin-1 finger loop interacts with two distinct conformations of active rhodopsin

Elgeti

Kazmin

Rose

et al. 2018

Journal of Biological Chemistry

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Signaling of the prototypical G protein coupled receptor (GPCR) rhodopsin through its cognate G protein transducin (G t ) is quenched when arrestin binds to the activated receptor. Although the overall architecture of the rhodopsin-arrestin complex is known, many questions regarding its specificity remain unresolved. Here, using FTIR difference spectroscopy and a dual pH/ peptide titration assay, we show that rhodopsin maintains certain flexibility upon binding the "finger loop" of visual arrestin (prepared as synthetic peptide ArrFL-1). We found that two distinct complexes can be stabilized depending on the protonation state of E3.49 in the conserved (D)ERY motif. Both complexes exhibit different interaction modes and affinities of ArrFL-1 binding. The plasticity of the receptor within the rhodopsin/ArrFL-1 complex stands in contrast to the complex with the C-terminus of the G t α-subunit (GαCT), which stabilizes only one specific substate out of the conformational ensemble. However, GαCT binding and both ArrFL-1 binding modes involve a direct interaction to conserved R3.50, as determined by site-directed mutagenesis. Our findings highlight the importance of receptor conformational flexibility and cytoplasmic proton uptake for modulation of rhodopsin signaling and thereby extend the picture provided by crystal structures of the rhodopsin/arrestin and rhodopsin/ArrFL-1 complexes. Furthermore, the two binding modes of ArrFL-1 identified here involve motifs of conserved amino acids, which indicates that our results may have elucidated a common modulation mechanism of class A GPCR-G protein/-arrestin signaling.Unlike other class A GPCRs the photoreceptor rhodopsin contains the light-sensitive cofactor retinal as a ligand, which is covalently bound to the opsin apoprotein. Upon light-induced cis/trans isomerization of retinal and subsequent alterations within the binding pocket, the signal propagates via GPCR-conserved interhelical networks towards the cytoplasmic surface of the receptor, where major structural rearrangements take place. The most prominent structural change is the rotational outward tilt of transmembrane (TM) helix 6, which opens a cytoplasmic binding crevice and thus constitutes the main prerequisite for binding and activation of signaling via the G protein transducin (1, 2). Even though first identified in rhodopsin, for many other GPCRs homologous structural changes have been shown to exist, and a common structural and functional framework for GPCRs is being developed (3).

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Formation and Decay of the Arrestin·Rhodopsin Complex in Native Disc Membranes

Cited by 13 publications

References 57 publications

Functional trade-offs and environmental variation shaped ancient trajectories in the evolution of dim-light vision

Functional trade-offs and environmental variation shaped ancient trajectories in the evolution of dim-light vision

C-edge loops of arrestin function as a membrane anchor

The arrestin-1 finger loop interacts with two distinct conformations of active rhodopsin

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