The Ca<sup>2+</sup> Permeation Mechanism of the Ryanodine Receptor Revealed by a Multi-Site Ion Model

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

doi:10.1101/682328

Cited by 8 publications

(12 citation statements)

References 52 publications

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“…For example, in the Ca v 1.1 ion channel, rings of four Glu residues and eight carbonyl oxygens provide a Ca 2+ selective filter ( 23 ). Likewise, in the cardiac RyR, three rings each containing four acidic residues select for the permeation of solvated Ca 2+ ions ( 24 ). In P-type ATPases such as the sarcoplasmic reticulum Ca 2+ ATPase, polar interactions between Ca 2+ ions and the carbonyl groups and side chains of surrounding amino acids have been observed ( 25 ).…”

Section: Resultsmentioning

confidence: 99%

The structural basis of bacterial manganese import

et al. 2021

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Metal ions are essential for all forms of life. In prokaryotes, ATP-binding cassette (ABC) permeases serve as the primary import pathway for many micronutrients including the first-row transition metal manganese. However, the structural features of ionic metal transporting ABC permeases have remained undefined. Here, we present the crystal structure of the manganese transporter PsaBC from Streptococcus pneumoniae in an open-inward conformation. The type II transporter has a tightly closed transmembrane channel due to “extracellular gating” residues that prevent water permeation or ion reflux. Below these residues, the channel contains a hitherto unreported metal coordination site, which is essential for manganese translocation. Mutagenesis of the extracellular gate perturbs manganese uptake, while coordination site mutagenesis abolishes import. These structural features are highly conserved in metal-specific ABC transporters and are represented throughout the kingdoms of life. Collectively, our results define the structure of PsaBC and reveal the features required for divalent cation transport.

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Section: Resultsmentioning

confidence: 99%

The structural basis of bacterial manganese import

et al. 2021

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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, 44 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

Preprint

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The calcium release-activated calcium (CRAC) 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 WT. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously undescribed 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 8 publications

References 52 publications

The structural basis of bacterial manganese import

The structural basis of bacterial manganese import

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 8 publications

References 52 publications

The structural basis of bacterial manganese import

The structural basis of bacterial manganese import

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

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