Conformational transitions and ligand-binding to a muscle-type nicotinic acetylcholine receptor

Zarkadas, Eleftherios; Pebay‐Peyroula, Eva; Thompson, Mackenzie J.; Schoehn, Guy; Uchański, Tomasz; Steyaert, Jan; Chipot, Christophe; Dagognet, François; Baenziger, John E.; Nury, Hugues

doi:10.1016/j.neuron.2022.01.013

Cited by 54 publications

(110 citation statements)

References 94 publications

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“…Annular sites for phospholipids are also observed in each of the Torpedo nAChR structures solved to date, including a conserved inner leaflet site adjacent to, but in some cases overlapping with the high affinity cholesterol sites noted above [ 57 , 61 , 62 ]. In most cases, the phosphate of the modeled phosphatidylcholine (PC) is sandwiched between two positively charged residues, a conserved arginine located just after the M3 𝛼-helix from the principal subunit and a lysine, arginine, or histidine from the complimentary M4 𝛼-helix (e.g., 𝛼R301 and 𝛾K449 at the 𝛼-𝛾 site; Figure 3 ).…”

Section: Introductionmentioning

confidence: 99%

“…Note that the binding pose of the choline moiety of the headgroup varies from subunit to subunit and from structures to structure likely because there are no specific coordinating interactions. Furthermore, PC or PA bind quickly to this motif and remain bound for the duration of all trajectories in molecular dynamics (MD) simulations [ 62 ]. This site is connected to a salt bridge between M4 and the back of the M2 𝛼-helix, previously shown to be important in channel gating in the human adult muscle nAChR [ 63 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is notable that the outermost M4 𝛼-helix from 𝛼 𝛿 , and to a lesser extent from 𝛼 𝛾 , tilts away from the rest of the TMD in agonist bound structures. The outward tilt of M4 allows the acyl chain of an outer leaflet phospholipid to enter the void between the end of M4 and the rest of the TMD where it contacts the strictly conserved Cys-loop FPF motif [ 62 ]. The outward tilt of M4 allows the inhibitor d-tubocurarine to bind in the same cavity [ 57 ].…”

Section: Introductionmentioning

confidence: 99%

“…Another striking feature of the various Torpedo structures is that, while there is conservation of phospholipid binding sites, which hints at a role for such sites in channel function, the bound cholesterol observed in structures reported by Rahman et al [ 57 ] are not observed in all Torpedo structures, particularly those reported by Zarkadas et al [ 62 ]. The absence of bound cholesterol in the latter structures likely reflects the fact that Zarkadas et al washed the detergent-solubilized nAChR extensively with detergent-solubilized soybean azolectin during purification leading to cholesterol–phospholipid exchange.…”

Section: Introductionmentioning

confidence: 99%

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Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

et al. 2022

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Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function and may help shape synaptic communication. Increasing structural and biophysical data reveal sites for lipid binding to pLGICs. Here, we update our evolving understanding of pLGIC–lipid interactions highlighting newly identified modes of lipid binding along with the mechanistic understanding derived from the new structural data.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

et al. 2022

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“…(8)(9)(10)(11)(12)(13)(14)(15)) and rate-equilibrium free energy relationships (REFER) (16)(17)(18)(19) in combination with cryo-electron and X-ray structures of cationic and anionic pLGICs (e.g. (7,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)) have shed light on the molecular interactions and structural changes that translate agonist binding to receptor activation. The mechanism for channel activation is broadly conserved across the pLGIC family and comprises an agonist-induced global twist in the ECD and TMD, leading to channel opening.…”

Section: Introductionmentioning

confidence: 99%

Structural and temporal basis for agonism in the α4β2 nicotinic acetylcholine receptor

Oliveira

Bermúdez

Gallagher

et al. 2022

Preprint

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Despite decades of study, the structural mechanisms underpinning agonist efficacy in pentameric ligand-gated ion channels remain poorly understood. Here, a combination of extensive equilibrium and dynamical-nonequilibrium molecular dynamics simulations was used to obtain a detailed description of the structural and dynamic changes induced within the human α4β2 nicotinic acetylcholine receptor by a full and a partial agonist, namely acetylcholine and nicotine, and map how these rearrangements propagate within this receptor. These simulations reveal how the agonists modulate the patterns associated with intra and inter-domain communication and the evolution of the agonist-specific structural rearrangements. For the first time, we show that full and partial agonists, although generally using similar routes for through-receptor signal transmission, induce different amplitudes of conformational rearrangements in key functional motifs, thus impacting the rates of signal propagation within the protein. The largest agonist-induced conformational differences are located in the Cys loop, loops C and α1-β1 in the α4 subunit, loops F and β1-β2 in the β2 subunit and in the extracellular selectivity filter.

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Two residues determine nicotinic acetylcholine receptor requirement for RIC‐3

Noonan

Beech

2023

Protein Science

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Nicotinic acetylcholine receptors (N‐AChRs) mediate fast synaptic signalling and are members of the pentameric ligand‐gated ion channel (pLGIC) family. They rely on a network of accessory proteins in vivo for correct formation and transport to the cell surface. RIC‐3 is an endoplasmic reticulum protein that physically interacts with nascent pLGIC subunits and promotes their oligomerization. It is not known why some N‐AChRs require RIC‐3 in heterologous expression systems, while others do not. Previously we reported that the ACR‐16 N‐AChR from the parasitic nematode Dracunculus medinensis does not require RIC‐3 in Xenopus laevis oocytes. This is unusual because all other nematode ACR‐16, like the closely related Ascaris suum ACR‐16, require RIC‐3. Their high sequence similarity limits the number of amino acids that may be responsible, and the goal of this study was to identify them. A series of chimeras and point mutations between A. suum and D. medinensis ACR‐16, followed by functional characterization with electrophysiology, identified two residues that account for a majority of the receptor requirement for RIC‐3. ACR‐16 with R/K159 in the cys‐loop and I504 in the C‐terminal tail did not require RIC‐3 for functional expression. Mutating either of these to R/K159E or I504T, residues found in other nematode ACR‐16, conferred a RIC‐3 requirement. Our results agree with previous studies showing that these regions interact and are involved in receptor synthesis. Although it is currently unclear what precise mechanism they regulate, these residues may be critical during specific subunit folding and/or assembly cascades that RIC‐3 may promote.This article is protected by copyright. All rights reserved.

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Conformational transitions and ligand-binding to a muscle-type nicotinic acetylcholine receptor

Cited by 54 publications

References 94 publications

Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

Structural and temporal basis for agonism in the α4β2 nicotinic acetylcholine receptor

Two residues determine nicotinic acetylcholine receptor requirement for RIC‐3

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