The LILI Motif of M3-S2 Linkers Is a Component of the NMDA Receptor Channel Gate

Ladislav, Marek; Černý, Jiří; Krůšek, Jan; Hořák, Martin; Balík, Aleš; Vyklicky, Ladislav

doi:10.3389/fnmol.2018.00113

Cited by 26 publications

(40 citation statements)

References 47 publications

(89 reference statements)

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“…Importantly, a greater amount of energy transfer is required to open the channel even when in the 'fast' pathway ( Figures 4D & 4H). Hence, the mechanically pulling entailing the M3-S2 is directly involved in opening the ion channel, consistent with its central role in iGluR gating ( Figures 3A & 3B) (Kazi et al, 2014;Ladislav et al, 2018).…”

Section: Lbd Coupling To the M3 Segments Determines The Energy Of Thesupporting

confidence: 63%

NMDA receptors require multiple pre-opening gating steps for efficient synaptic activity

Amin

Gochman

et al. 2020

Preprint

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NMDA receptors (NMDAR) are glutamate-gated ion channels that mediate the majority of fast excitatory synaptic transmission in the nervous system. A central feature of NMDAR physiology is the opening of the ion channel driven by presynaptically-released glutamate. Using glutamate applications to outside-out patches containing a single NMDAR in the continuous presence of the co-agonist glycine, we find that agonist-bound receptors transition to the open state via two conformations, an 'unconstrained pre-active' state that can rapidly transition to the open state and contributes to synaptic events, and a 'constrained pre-active' state that requires more energy and hence time to open and does not contribute to fast signaling. To define how agonist binding might drive these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for the GluN1 and GluN2A subunits. Displacements of the central pore-forming M3 segments define the energy of fast channel opening. However, to enter the unconstrained conformation and contribute to fast signaling, a peripheral helix, the GluN2 pre-M1, must be displaced before the M3 segments move. This pre-M1 displacement is facilitated by the flexibility of another nearby peripheral element, the GluN1 and GluN2A S2-M4. We conclude that peripheral structural elements -pre-M1 and S2-M4 -work in concert to remove constraints and prime the channel for rapid opening, thus facilitating fast synaptic transmission. 214 words. McDaniel et al., 2020). The S2-M4 linker/M4 segment also regulates gating (Amin et al., 2017;Yelshanskaya et al., 2017;Shi et al., 2019). Still, the energetics and timing of these non-pore forming elements to receptor gating remains incomplete.Here, we address the gating mechanism in NMDARs. At most synapses, NMDARs are obligate hetero-tetramers composed of two GluN1 and two GluN2 (A-D) subunits. To define conformational changes between agonist binding and pore opening, we rapidly applied glutamate to outside-out patches containing single NMDARs and assessed the time between when glutamate was first applied to when the channel first opened ('latency to 1 st opening', see Materials and Methods) (Aldrich et al., 1983). With this approach, we identified that wild type GluN1/GluN2A NMDARs, in the transition from agonist-bound closed to the open state, transitions through one of two pre-active states: an 'unconstrained' state that can rapidly transition to the open state and contributes to fast synaptic signaling, and a 'constrained' state that slowly transitions to the open state, presumably due to higher energy requirements, and does not contribute to fast signaling. Further, by decoupling the LBD from the TMD for each specific LBD-TMD linker (S1-M1, M3-S2, and S2-M4, Figure 1B & 1C) (Niu et al., 2004;Kazi et al., 2014), we show that the non-pore forming linkers uniquely influence pore-opening by altering the stability of these pre-active conformations. Thus, our results highlight the temporal and coordinated movements from agonist binding to io...

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Section: Lbd Coupling To the M3 Segments Determines The Energy Of Thesupporting

confidence: 63%

NMDA receptors require multiple pre-opening gating steps for efficient synaptic activity

Amin

Gochman

et al. 2020

Preprint

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“…More specifically, PBs are also useful for analysis of protein flexibility (Craveur et al 2015), for instance, using molecular dynamics in the specific cases of integrins (Jallu, Poulain, Fuchs, Kaplan & de Brevern 2012;Jallu, Poulain, Fuchs, Kaplan & de Brevern 2014;Goguet, Narwani, Petermann, Jallu & de Brevern 2017), Duffy Antigen Chemokine Receptor (DARC) protein (de Brevern et al 2005), KiSS1-derived peptide receptor (KISS1R) (Chevrier et al 2013), HIV-1 capsid protein (Craveur et al 2019), α-1,4-glycosidic hydrolase (Pandurangan et al 2019), NMDA Receptor Channel Gate (Ladislav et al 2018), and analysis of local dynamics of proteins and DNA estimated from crystallographic B-factors . These researches motivated us to go further to design the analysis of large-scale molecular dynamics simulation from a large number of folds, in order to understand the structural evolution of the local conformation of each region (see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Discrete analyses of protein dynamics

Narwani

Craveur

Shinada

et al. 2019

Journal of Biomolecular Structure and Dynamics

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Protein structures are highly dynamic macromolecules. This dynamics is often analysed through experimental and/or computational methods only for an isolated or a limited number of proteins. Here, we explore large-scale protein dynamics simulation to observe dynamics of local protein conformations using different perspectives. We analysed molecular dynamics to investigate protein flexibility locally, using classical approaches such as RMSf, solvent accessibility, but also innovative approaches such as local entropy. Firstly, we focussed on classical secondary structures and analysed specifically how βstrand, β−turns, and bends evolve during molecular simulations. We underlined interesting specific bias between β−turns and bends, which are considered as same category, while their dynamics show differences. Secondly, we used a structural alphabet that is able to approximate every part of the protein structures conformations, namely Protein Blocks (PBs) to analyse (i) how each initial local protein conformations evolve during dynamics and (ii) if some exchange can exist among these PBs. Interestingly, the results are largely complex than simple regular/rigid and coil/flexible exchange.

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“…As previously shown, analysis with local protein conformation is often different from global analysis. For instance, analyses of molecular dynamics simulation showed large difference between RMSf and N eq [13,16,18,65], with the correlation being slightly higher than 0.4. Therefore, the correlation between N eq and the prediction values was not expected to be much better.…”

Section: Comparison Of N Eq With Prediction Resultsmentioning

confidence: 99%

“…In this field, protein blocks (PBs), structural alphabets have been particularly successful [12]. Recently, they have been used to analyze flexibility of protein structures [13,14] and molecular dynamics simulations [15], e.g., integrins [16], HIV-1 capsid protein [17], and the N-methyl-D-aspartate receptor (NMDA) receptor channel gate [18]. Nonetheless, all these studies did not look at an essential part of the proteins.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

Brevern

2020

Biomolecules

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Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that encompasses rigid and flexible regions-to disorder regions; the latter being not accessible through classical crystallographic methodologies. In X-ray structures, the notion of order is dictated by access to resolved atom positions, providing rigidity and flexibility information with low and high experimental B-factors, while disorder is associated with the missing (non-resolved) residues. Nonetheless, some rigid regions can be found in disorder regions. Using ensembles of IDPs, their local conformations were analyzed in the light of a structural alphabet. An entropy index derived from this structural alphabet allowed us to propose a continuum of states from rigidity to flexibility and finally disorder. In this study, the analysis was extended to comparing these results to disorder predictions, underlying a limited correlation, and so opening new ideas to characterize and predict disorder.

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The LILI Motif of M3-S2 Linkers Is a Component of the NMDA Receptor Channel Gate

Cited by 26 publications

References 47 publications

NMDA receptors require multiple pre-opening gating steps for efficient synaptic activity

NMDA receptors require multiple pre-opening gating steps for efficient synaptic activity

Discrete analyses of protein dynamics

Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

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