The Ca2+ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Zhang, Aihua; Yu, Hua-Zhong; Liu, Chunhong; Song, Chen

doi:10.1038/s41467-020-14573-w

Cited by 45 publications

(63 citation statements)

References 62 publications

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“…In other words, the AMPA receptor channel is minimally selective and has one of the simplest observed SFs comprising only two residues (Q586 and Q587). The mechanism of cation selection in the AMPA receptor also shows some similarity with the one of ryanodine receptor, where four Q4863 at the constriction zone act as a charge SF for selecting cations over anions, as suggested by previous MD simulations ( 44 , 45 ).…”

Section: Discussionsupporting

confidence: 54%

Nonselective cation permeation in an AMPA-type glutamate receptor

Biedermann

Braunbeck

Plested

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Fast excitatory synaptic transmission in the central nervous system relies on the AMPA-type glutamate receptor (AMPAR). This receptor incorporates a nonselective cation channel, which is opened by the binding of glutamate. Although the open pore structure has recently became available from cryo-electron microscopy (Cryo-EM), the molecular mechanisms governing cation permeability in AMPA receptors are not understood. Here, we combined microsecond molecular dynamic (MD) simulations on a putative open-state structure of GluA2 with electrophysiology on cloned channels to elucidate ion permeation mechanisms. Na+, K+, and Cs+ permeated at physiological rates, consistent with a structure that represents a true open state. A single major ion binding site for Na+ and K+ in the pore represents the simplest selectivity filter (SF) structure for any tetrameric cation channel of known structure. The minimal SF comprised only Q586 and Q587, and other residues on the cytoplasmic side formed a water-filled cavity with a cone shape that lacked major interactions with ions. We observed that Cl− readily enters the upper pore, explaining anion permeation in the RNA-edited (Q586R) form of GluA2. A permissive architecture of the SF accommodated different alkali metals in distinct solvation states to allow rapid, nonselective cation permeation and copermeation by water. Simulations suggested Cs+ uses two equally populated ion binding sites in the filter, and we confirmed with electrophysiology of GluA2 that Cs+ is slightly more permeant than Na+, consistent with serial binding sites preferentially driving selectivity.

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Section: Discussionsupporting

confidence: 54%

Nonselective cation permeation in an AMPA-type glutamate receptor

Biedermann

Braunbeck

Plested

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…A new Ca 2+ model that reduces the strong interactions here may be useful. Recently, an updated Ca 2+ model successfully simulated the translocation of Ca 2+ through the ryanodine receptor ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

Structural and energetic analysis of metastable intermediate states in the E1P–E2P transition of Ca ²⁺ -ATPase

Kobayashi

Matsunaga

Jung

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Sarcoplasmic reticulum (SR) Ca2+-ATPase transports two Ca2+ ions from the cytoplasm to the SR lumen against a large concentration gradient. X-ray crystallography has revealed the atomic structures of the protein before and after the dissociation of Ca2+, while biochemical studies have suggested the existence of intermediate states in the transition between E1P⋅ADP⋅2Ca2+ and E2P. Here, we explore the pathway and free energy profile of the transition using atomistic molecular dynamics simulations with the mean-force string method and umbrella sampling. The simulations suggest that a series of structural changes accompany the ordered dissociation of ADP, the A-domain rotation, and the rearrangement of the transmembrane (TM) helices. The luminal gate then opens to release Ca2+ ions toward the SR lumen. Intermediate structures on the pathway are stabilized by transient sidechain interactions between the A- and P-domains. Lipid molecules between TM helices play a key role in the stabilization. Free energy profiles of the transition assuming different protonation states suggest rapid exchanges between Ca2+ ions and protons when the Ca2+ ions are released toward the SR lumen.

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“…However, how the mutation of residue 210 allosterically affects K270 is still not clear. Further simulations and analysis are undergoing to focus on the selectivity difference between the WT and the L210F mutant using a new calcium model, ( Zhang et al, 2020 ), which will hopefully provide a better understanding on this aspect.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study

Zhang

Liu

et al. 2021

Front. Mol. Biosci.

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The calcium release-activated calcium channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the wild-type. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously unobserved feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.

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The Ca2+ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Cited by 45 publications

References 62 publications

Nonselective cation permeation in an AMPA-type glutamate receptor

Nonselective cation permeation in an AMPA-type glutamate receptor

Structural and energetic analysis of metastable intermediate states in the E1P–E2P transition of Ca ²⁺ -ATPase

The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study

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The Ca2+ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Cited by 45 publications

References 62 publications

Nonselective cation permeation in an AMPA-type glutamate receptor

Nonselective cation permeation in an AMPA-type glutamate receptor

Structural and energetic analysis of metastable intermediate states in the E1P–E2P transition of Ca 2+ -ATPase

The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study

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Structural and energetic analysis of metastable intermediate states in the E1P–E2P transition of Ca ²⁺ -ATPase