Mapping co‐regulatory interactions among ligand‐binding sites in ryanodine receptor 1

Chirasani, Venkat R.; Popov, Konstantin; Meissner, Gerhard; Dokholyan, Nikolay V.

doi:10.1002/prot.26228

Cited by 3 publications

(13 citation statements)

References 33 publications

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“…Second, a previous study reported that although distributed $10 nm away from RBD, the SARS-CoV-2 polybasic cleavage site can enhance the RBD-ACE2 binding affinity via electrostatic interactions. 43 We conducted a comparative analysis of our approach with Ohm, a well-established method [44][45][46] for mapping allosteric communications. Both methods successfully highlight the significance of K528 in the main allosteric pathway (Figure S4A), aligning with findings from previous studies.…”

Section: Discussionmentioning

confidence: 99%

Allosteric pathways of SARS and SARS‐CoV‐2 spike protein identified by neural relational inference

Hu,

Li,

Wang

2024

Proteins

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The receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein must undergo a crucial conformational transition to invade human cells. It is intriguing that this transition is accompanied by a synchronized movement of the entire spike protein. Therefore, it is possible to design allosteric regulators targeting non‐RBD but hindering the conformational transition of RBD. To understand the allosteric mechanism in detail, we establish a computational framework by integrating coarse‐grained molecular dynamic simulations and a state‐of‐the‐art neural network model called neural relational inference. Leveraging this framework, we have elucidated the allosteric pathway of the SARS‐CoV‐2 spike protein at the residue level and identified the molecular mechanisms involved in the transmission of allosteric signals. The movement of D614 is coupled with that of Q321. This interaction subsequently influences the movement of K528/K529, ultimately coupling with the movement of RBD during conformational changes. Mutations that weaken the interactions within this pathway naturally block the allosteric signal transmission, thereby modulating the conformational transitions. This observation also offers a rationale for the distinct allosteric patterns observed in the SARS‐CoV spike protein. Our result provides a useful method for analyzing the dynamics of potential viral variants in the future.

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Section: Discussionmentioning

confidence: 99%

Allosteric pathways of SARS and SARS‐CoV‐2 spike protein identified by neural relational inference

Hu,

Li,

Wang

2024

Proteins

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“…This principle is used in the OHM server for the detection of allosteric pathways (Wang et al, 2020). Previously, analysis of such pathways in RyR1 structures revealed how the cytosolic calcium, ATP, and caffeine activate RyR1 (Chirasani et al, 2022). Here we have used the OHM server to explore the regulatory network of both ion-dependent allosteric pathways.…”

Section: Comparison Of Domain Positions In Different Ryr Statesmentioning

confidence: 99%

“…Both pathways displayed several branches that partially fluctuated among model structures. Notably, most branches comprised residues either of the ATP binding site, known to support the calcium-dependent activation (des Georges et al, 2016;Chirasani et al, 2022), or of the S45 linker, known to participate in the regulation of channel gating (Murayama et al, 2011;Gomez et al, 2016).…”

Section: The Inhibition Networkmentioning

confidence: 99%

“…All branches comprised the CTD, the U-motif, and the S6 helix. Six branches involved one or more residues of the ATP-binding site, two branches involved residues of the caffeine/xanthine binding site known to support the calcium-dependent activation (des Georges et al, 2016;Chirasani et al, 2022), and three branches involved residues of the S45 linker known to participate in the regulation of channel gating (Murayama et al, 2011;Gomez et al, 2016). Individual model structures contained 1 -4 branches in various proportions.…”

Section: The Activation Networkmentioning

confidence: 99%

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Structure-based mechanism of RyR channel operation by calcium and magnesium ions

Zahradníková,

Pavelková,

Sabo

et al. 2024

Preprint

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Ryanodine receptors (RyRs) serve for excitation-contraction coupling in skeletal and cardiac muscle cells in a noticeably different way, not fully understood at the molecular level. We addressed the structure of skeletal (RyR1) and cardiac (RyR2) isoforms relevant to the gating by divalent ions (M2+). The bioinformatics analysis of 43 cryo-EM RyR structures ascertained the EF1 and EF2 loops as a moderate-affinity non-specific M2+binding site interacting with the S23 loop of neighbor monomer stronger in RyR1 than RyR2. The EF1/EF2 loops were allosterically coupled to the S6 gate by two parallel pathways. The intra-monomeric pathway uses the U-motif, ATP binding site, S45 linker, and S6 helix, shared with the Ca2+-activation pathway in both RyR isoforms. The inter-monomeric pathway, prominent in RyR1, passes through the S23* loop of the neighbor monomer (*) andviathe U-motif* to the S6* gate either directly or through the S45* linker or CFF* binding site. The structural pieces of evidence for the M2+-binding activation and inhibition sites and their interacting allosteric networks were implemented in the model of RyR operation based on statistical mechanics, MWC theorem, and Markov processes. This model defines allosterically coupled closed, open, and inactivated RyR macrostates common for both RyR isoforms and solves the relative occupancy of macrostates in dependence on cytosolic M2+concentrations. The model approximated the single-channel open probability data for RyR1 and RyR2 of several species obtained in the presence or absence of ATP and luminal calcium. The proposed platform of RyR operation interprets the structural and functional data of mammalian RyR channels on common grounds.

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“…The Ca 2+ activation site (3667–4253), caffeine-activation site (around W4645) and luminal Ca 2+ sensor (around E4872) are in the vicinity of the four mutation sites and close to the S6/C-terminal domain junction ( Zhang et al, 2014 ; Murayama et al, 2018 ). Allosteric interaction predictions have been used to show that cytoplasmic Ca 2+ and caffeine binding is communicated to the channel gate via a cascade of overlapping interactions that control RyR1 activity ( Chirasani et al, 2021 ) and are likely to similarly influence RyR2 activity.…”

Section: High Resolution Structural Analysis Of Catecholaminergic Pol...mentioning

confidence: 99%

Molecular Changes in the Cardiac RyR2 With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Dulhunty

2022

Front. Physiol.

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The cardiac ryanodine receptor Ca2+ release channel (RyR2) is inserted into the membrane of intracellular sarcoplasmic reticulum (SR) myocyte Ca2+ stores, where it releases the Ca2+ essential for contraction. Mutations in proteins involved in Ca2+ signaling can lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). The most common cellular phenotype in CPVT is higher than normal cytoplasmic Ca2+ concentrations during diastole due to Ca2+ leak from the SR through mutant RyR2. Arrhythmias are triggered when the surface membrane sodium calcium exchanger (NCX) lowers cytoplasmic Ca2+ by importing 3 Na+ ions to extrude one Ca2+ ion. The Na+ influx leads to delayed after depolarizations (DADs) which trigger arrhythmia when reaching action potential threshold. Present therapies use drugs developed for different purposes that serendipitously reduce RyR2 Ca2+ leak, but can adversely effect systolic Ca2+ release and other target processes. Ideal drugs would specifically reverse the effect of individual mutations, without altering normal channel function. Such drugs will depend on the location of the mutation in the 4967-residue monomer and the effect of the mutation on local structure, and downstream effects on structures along the conformational pathway to the pore. Such atomic resolution information is only now becoming available. This perspective provides a summary of known or predicted structural changes associated with a handful of CPVT mutations. Known molecular changes associated with RyR opening are discussed, as well one study where minute molecular changes with a particular mutation have been tracked from the N-terminal mutation site to gating residues in the channel pore.

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Mapping co‐regulatory interactions among ligand‐binding sites in ryanodine receptor 1

Cited by 3 publications

References 33 publications

Allosteric pathways of SARS and SARS‐CoV‐2 spike protein identified by neural relational inference

Allosteric pathways of SARS and SARS‐CoV‐2 spike protein identified by neural relational inference

Structure-based mechanism of RyR channel operation by calcium and magnesium ions

Molecular Changes in the Cardiac RyR2 With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

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