Cryo-EM structure of the native rhodopsin dimer in nanodiscs

Zhao, Dorothy Yanling; Pöge, Matthias; Morizumi, Takefumi; Gulati, Sahil; Eps, Ned Van; Zhang, Jianye; Miszta, Przemysław; Filipek, Sławomir; Mahamid, Julia; Plitzko, Jürgen M.; Baumeister, Wolfgang; Ernst, Oliver P.; Palczewski, Krzysztof

doi:10.1074/jbc.ra119.010089

Cited by 67 publications

(56 citation statements)

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“…Recent experimental evidence have suggested that more than 70% of Rh is in dimeric or higher oligomeric state(s) existing in a dynamic equilibrium [13,18,25]. Based on these findings and our current results, the H1/H8 dimer forms transient row structure through lipid raft-based interaction between the dimers, which appears consistent with results from recent studies [13,42,43]. In addition, we found that the nano-sized domains of saturated lipids with cholesterols (raftophilic lipids, i.e., lipid rafts) were also key factors in forming Rh-dimer row structures with H1/H8 dimers.…”

Section: Discussionsupporting

confidence: 93%

“…In our model, the model of H1/H8 dimer was constructed based on the crystal structure of the activated form of the Rh-dimer [30]. Recently, photoactivation of Rh was known to induce a structural rearrangement, for example, an increase in the distance between specific helices of Rh [43,46,47]. However, such local deformations did not affect the global geometric shape of Rh-dimer, and the structures around H1/H8 interface were highly conserved.…”

Section: Discussionmentioning

confidence: 99%

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Affinity of rhodopsin to raft enables the aligned oligomer formation from dimers: Coarse-grained molecular dynamics simulation of disk membranes

Kaneshige¹,

Hayashi²,

Morigaki³

et al. 2020

PLoS ONE

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The visual photopigment protein rhodopsin (Rh) is a typical G protein-coupled receptor (GPCR) that initiates the phototransduction cascade in retinal disk membrane of rod-photoreceptor cells. Rh molecule has a tendency to form dimer, and the dimer tends to form rows, which is suggested to heighten phototransduction efficiency in single-photon regime. In addition, the dimerization confers Rh an affinity for lipid raft, i.e. raftophilicity. However, the mechanism by which Rh-dimer raftophilicity contributes to the organization of the higher order structure remains unknown. In this study, we performed coarse-grained molecular dynamics simulations of a disk membrane model containing unsaturated lipids, saturated lipids with cholesterol, and Rh-dimers. We described the Rh-dimers by two-dimensional particle populations where the palmitoyl moieties of each Rh exhibits raftophilicity. We simulated the structuring of Rh in a disk for two types of Rh-dimer, i.e., the most and second most stable Rh dimers, which exposes the raftophilic regions at the dimerization-interface (H1/H8 dimer) and two edges away from the interface (H4/H5 dimer), respectively. Our simulations revealed that only the H1/H8 dimer could form a row structure. A small number of raftophilic lipids recruited to and intercalated in a narrow space between H1/H8 dimers stabilize the side-by-side interaction between dimers in a row. Our results implicate that the nano-sized lipid raft domains act as a "glue" to organize the long row structures of Rhdimers.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Affinity of rhodopsin to raft enables the aligned oligomer formation from dimers: Coarse-grained molecular dynamics simulation of disk membranes

Kaneshige¹,

Hayashi²,

Morigaki³

et al. 2020

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Recent experimental evidence have suggested that more than 70% of Rh is in dimeric or higher oligomeric state(s) existing in a dynamic equilibrium [13,18,19]. Based on these findings and our current results, the H1/H8 dimer forms transient row structure through lipid raft-based interaction between the dimers, which appears consistent with results from recent studies [13,31,32]. In addition, we found that the nano-sized domains of saturated lipids with cholesterols (raftophilic lipids, i.e., lipid rafts) were also key factors in forming Rh-dimer row structures with H1/H8 dimers.…”

Section: Discussionsupporting

confidence: 93%

Affinity of rhodopsin to raft enables the aligned oligomer formation from dimers: Coarse-grained molecular dynamics simulation of disk membranes

Kaneshige

Hayashi

Morigaki

et al. 2019

Preprint

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24 The visual photopigment protein rhodopsin (Rh) is a typical G protein-coupled receptor 25 (GPCR) that initiates the phototransduction cascade in retinal disk membrane of 26 rod-photoreceptor cells. Rh molecule has a tendency to form dimer, and the dimer tends 27 to form rows, which is suggested to heighten phototransduction efficiency in 28 single-photon regime. In addition, the dimerization confers Rh an affinity for lipid raft, 29 i.e. raftophilicity. However, the mechanism by which Rh-dimer raftophilicity 30 contributes to the organization of the higher order structure remains unknown. In this 31 study, we performed coarse-grained molecular dynamics simulations of a disk 32 membrane model containing unsaturated lipids, saturated lipids with cholesterol, and 33 Rh-dimers. We described the Rh-dimers by two-dimensional particle populations where 34 the palmitoyl moieties of each Rh exhibits raftophilicity. We simulated the structuring 35 of Rh in a disk for two types of Rh-dimer, i.e., the most and second most stable Rh 36 dimers, which exposes the raftophilic regions at the dimerization-interface (H1/H8 37 dimer) and two edges away from the interface (H4/H5 dimer), respectively. Our 38 simulations revealed that only the H1/H8 dimer could form a row structure. A small 39 number of raftophilic lipids recruited to and intercalated in a narrow space between 40 H1/H8 dimers stabilize the side-by-side interaction between dimers in a row. Our results 41 implicate that the nano-sized lipid raft domains act as a "glue" to organize the long row 42 structures of Rh-dimers. 43 44 INTRODUCTION 45 The visual pigment rhodopsin (Rh) initiates the phototransduction cascade in vertebrate 46 disk membranes of rod photoreceptor cells. Rh is a prototypical seven-transmembrane 47 G protein-coupled receptor (GPCR) and is highly concentrated in the disk membrane, 48 occupying approximately 30% of the total disk membrane area [1,2]. 49Similar to many other GPCRs, Rh is doubly palmitoylated (C16:0) at the 50 C-terminus of the juxta-membrane eighth-helix (H8) [3]. The tandem palmitoyls are 51 known to be a robust raft-targeting signal for membrane proteins [4][5][6][7][8][9]. However, 52 despite having two palmitoyls, Rh prefers polyunsaturated phospholipids because of its 53 rough intramembrane surface, which is similar to other membrane proteins [10,11].54 Thus, rhodopsin is inherently a non-raftophilic (raftophobic) membrane protein.55 Nevertheless, dimerization, which is stabilized by the binding of the cognate G protein 56 transducin, confers a high lipid raft affinity (raftophilicity) for Rh , i.e., the di-palmitoyl 57 modification at the C-terminus of H8 is prerequisite for the dimerization-dependent 58 raftophilicity of Rh [12]. Single-and semi-multimolecular observations on rhodopsin 59 dynamics in retinal disk have revealed that the oligomerization-induced raftophilicity of 60 Rh promotes spontaneous formation of raftophilic Rh-clusters [13]. 61 The organization and dynamics of Rh in the disk membrane have long been 62 debate...

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“…However, monomeric rhodopsin was found to be sufficient for binding of arrestin dimers [ 86 ]. Recently, native rhodopsin dimers were found in nanodiscs using cryo-electron microscopy [ 87 ].…”

Section: Effects Of Clr On Oligomerization Of Gpcrsmentioning

confidence: 99%

Allosteric Modulation of GPCRs of Class A by Cholesterol

Jakubík

El‐Fakahany

2021

IJMS

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G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30% of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Additionally, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

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Cryo-EM structure of the native rhodopsin dimer in nanodiscs

Cited by 67 publications

References 78 publications

Affinity of rhodopsin to raft enables the aligned oligomer formation from dimers: Coarse-grained molecular dynamics simulation of disk membranes

Affinity of rhodopsin to raft enables the aligned oligomer formation from dimers: Coarse-grained molecular dynamics simulation of disk membranes

Affinity of rhodopsin to raft enables the aligned oligomer formation from dimers: Coarse-grained molecular dynamics simulation of disk membranes

Allosteric Modulation of GPCRs of Class A by Cholesterol

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