An NMDA Receptor Gating Mechanism Developed from MD Simulations Reveals Molecular Details Underlying Subunit-Specific Contributions

Dai, Jixun; Zhou, Huan‐Xiang

doi:10.1016/j.bpj.2013.04.013

Cited by 39 publications

(67 citation statements)

References 53 publications

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“…All simulations were performed using NAMD version 2.9 (28) with CHARMM27 protein force field and CHARMM36 lipid force field (29). The simulation parameters were the same as those for the previous simulations (30,31).…”

Section: Homology Modeling and Molecular Dynamics Simulation-mentioning

confidence: 99%

The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Gan¹,

Dai

Zhou

et al. 2016

Journal of Biological Chemistry

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AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the central nervous system. Functional AMPARs are tetrameric complexes with a highly modular structure, consisting of four evolutionarily distinct structural domains: an amino-terminal domain (ATD), a ligand-binding domain (LBD), a channel-forming transmembrane domain (TMD), and a carboxyl-terminal domain (CTD). Here we show that the isolated TMD of the GluA1 AMPAR is fully capable of tetramerization. Additionally, removal of the extracellular domains from the receptor did not affect membrane topology or surface delivery. Furthermore, whereas the ATD and CTD contribute positively to tetramerization, the LBD presents a barrier to the process by reducing the stability of the receptor complex. These experiments pinpoint the TMD as the "tetramerization domain" for AMPARs, with other domains playing modulatory roles. They also raise intriguing questions about the evolution of iGluRs as well as the mechanisms regulating the biogenesis of AMPAR complexes.

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Section: Homology Modeling and Molecular Dynamics Simulation-mentioning

confidence: 99%

The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Gan¹,

Dai

Zhou

et al. 2016

Journal of Biological Chemistry

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“…This increased instability likely plays a key role in the functionality of the NMDAR (24)(25)(26)(27)(28)(29). Simulations of the NMDAR LBD suggest that the energy landscape of the protein is broad, even when bound to the primary agonist, indicating that there are many conformations that are weakly stable (19,38). In addition to the conformational changes experienced during normal receptor function, the protein can also unfold due to loss of stability of the folded state (18,39,40).…”

Section: Introductionmentioning

confidence: 95%

“…The NMDAR is unique among the glutamate receptors in that it forms hetero-tetrameric complexes using two glycine-binding GluN1 subunits, and two other subunits, either the glutamate-binding subunit GluN2 or the glycine-binding GluN3 subunit (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Each subunit comprises four main domains-the extracellular N-terminal domain, the ligand-binding domain (LBD), the intracellular C-terminal domain, and the transmembrane domain (14)(15)(16)(17)(18)(19). The LBD cleft, comprised of two lobes connected by a hinge, is responsible for inducing large conformational changes that control the opening and closing of the cation channel, allowing for the regulation of ion concentration into the cell (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

“…Each subunit comprises four main domains-the extracellular N-terminal domain, the ligand-binding domain (LBD), the intracellular C-terminal domain, and the transmembrane domain (14)(15)(16)(17)(18)(19). The LBD cleft, comprised of two lobes connected by a hinge, is responsible for inducing large conformational changes that control the opening and closing of the cation channel, allowing for the regulation of ion concentration into the cell (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Agonist binding induces a closing of the LBD cleft (see Fig.…”

Section: Introductionmentioning

confidence: 99%

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Conformational Transitions in the Glycine-Bound GluN1 NMDA Receptor LBD via Single-Molecule FRET

Cooper

Dolino

Jaurich

et al. 2015

Biophysical Journal

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The N-methyl-D-aspartate receptor (NMDAR) is a member of the glutamate receptor family of proteins and is responsible for excitatory transmission. Activation of the receptor is thought to be controlled by conformational changes in the ligand binding domain (LBD); however, glutamate receptor LBDs can occupy multiple conformations even in the activated form. This work probes equilibrium transitions among NMDAR LBD conformations by monitoring the distance across the glycine-bound LBD cleft using single-molecule Förster resonance energy transfer (smFRET). Recent improvements in photoprotection solutions allowed us to monitor transitions among the multiple conformations. Also, we applied a recently developed model-free algorithm called "step transition and state identification" to identify the number of states, their smFRET efficiencies, and their interstate kinetics. Reversible interstate conversions, corresponding to transitions among a wide range of cleft widths, were identified in the glycine-bound LBD, on much longer timescales compared to channel opening. These transitions were confirmed to be equilibrium in nature by shifting the distribution reversibly via denaturant. We found that the NMDAR LBD proceeds primarily from one adjacent smFRET state to the next under equilibrium conditions, consistent with a cleft-opening/closing mechanism. Overall, by analyzing the state-to-state transition dynamics and distributions, we achieve insight into specifics of long-lived LBD equilibrium structural dynamics, as well as obtain a more general description of equilibrium folding/unfolding in a conformationally dynamic protein. The relationship between such long-lived LBD dynamics and channel function in the full receptor remains an open and interesting question.

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“…Building on the structural snapshots provided by the crystal structures, we carried out molecular-dynamics simulations in which the LBD clefts were closed to induce channel opening (30,31). These simulations suggested that AMPA and NMDA receptors have similar gating mechanisms, with the M3-D2 linkers playing a crucial role in transmitting the action of LBD cleft closure into the opening of the channel pore.…”

Section: Introductionmentioning

confidence: 99%

Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating

Dai

Zhou

2016

Biophysical Journal

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NMDA receptors are tetrameric ligand-gated ion channels. In the continuous presence of saturating agonists, NMDA receptors undergo stationary gating, in which the channel stochastically switches between an open state that permits ion conductance and a closed state that prevents permeation. The ligand-binding domains (LBDs) of the four subunits are expected to have closed clefts in the channel-open state. On the other hand, there is little knowledge about the conformational status of the LBDs in the channel-closed state during stationary gating. To probe the latter conformational status, Kussius and Popescu engineered interlobe disulfide cross-links in NMDA receptors and found that the cross-linking produced stationary gating kinetics that differed only subtly from that produced by agonist binding. These authors assumed that the cross-linking immobilized the LBDs in cleft-closed conformations, and consequently concluded that throughout stationary gating, agonistbound LBDs also stayed predominantly in cleft-closed conformations and made only infrequent excursions to cleft-open conformations. Here, by calculating the conformational free energies of cross-linked and agonist-bound LBDs, we assess whether cross-linking actually traps the LBDs in cleft-closed conformations and delineate semiclosed conformations of agonist-bound LBDs that may potentially be thermodynamically and kinetically important during stationary gating. Our free-energy results show that the cross-linked LBDs are not locked in the fully closed form; rather, they sample semiclosed conformations almost as readily as the agonist-bound LBDs. Several lines of reasoning suggest that LBDs are semiclosed in the channel-closed state during stationary gating. Our free-energy simulations suggest possible structural details of such semiclosed LBD conformations, including intra-and intermolecular interactions that serve as alternatives to those in the cleft-closed conformations.

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An NMDA Receptor Gating Mechanism Developed from MD Simulations Reveals Molecular Details Underlying Subunit-Specific Contributions

Cited by 39 publications

References 53 publications

The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Conformational Transitions in the Glycine-Bound GluN1 NMDA Receptor LBD via Single-Molecule FRET

Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating

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