Type 2 Ryanodine Receptor Domain A Contains a Unique and Dynamic α-Helix That Transitions to a β-Strand in a Mutant Linked with a Heritable Cardiomyopathy

Amador, Fernando; Kimlicka, Lynn; Stathopulos, Peter B.; Gasmi-Seabrook, Geneviève M.C.; MacLennan, David H.; Petegem, Filip Van; Ikura, Mitsuhiko

doi:10.1016/j.jmb.2013.08.015

Cited by 38 publications

(46 citation statements)

References 49 publications

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“…For some of these missense variants, experimental data confirm their impact on RYR2 function. As an example, the missense mutation R176Q which is associated with arrhythmogenic right ventricular dysplasia type 2 causes structural alterations which are linked to channel dysfunction . In a mouse knock‐in model, the R176Q mutation predisposes the heart to catecholamine‐induced oscillatory calcium‐release events that trigger a calcium‐dependent ventricular arrhythmia …”

Section: Discussionsupporting

confidence: 83%

Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer

Schmitt

Molfenter

Laureano

et al. 2019

Intl Journal of Cancer

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Genomic sequencing projects unraveled the mutational landscape of head and neck squamous cell carcinoma (HNSCC) and provided a comprehensive catalog of somatic mutations. However, the limited number of significant cancer‐related genes obtained so far only partially explains the biological complexity of HNSCC and hampers the development of novel diagnostic biomarkers and therapeutic targets. We pursued a multiscale omics approach based on whole‐exome sequencing, global DNA methylation and gene expression profiling data derived from tumor samples of the HIPO‐HNC cohort (n = 87), and confirmed new findings with datasets from The Cancer Genome Atlas (TCGA). Promoter methylation was confirmed by MassARRAY analysis and protein expression was assessed by immunohistochemistry and immunofluorescence staining. We discovered a set of cancer‐related genes with frequent somatic mutations and high frequency of promoter methylation. This included the ryanodine receptor 2 (RYR2), which showed variable promoter methylation and expression in both tumor samples and cell lines. Immunohistochemical staining of tissue sections unraveled a gradual loss of RYR2 expression from normal mucosa via dysplastic lesion to invasive cancer and indicated that reduced RYR2 expression in adjacent tissue and precancerous lesions might serve as risk factor for unfavorable prognosis and upcoming malignant conversion. In summary, our data indicate that impaired RYR2 function by either somatic mutation or epigenetic silencing is a common event in HNSCC pathogenesis. Detection of RYR2 expression and/or promoter methylation might enable risk assessment for malignant conversion of dysplastic lesions.

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Section: Discussionsupporting

confidence: 83%

Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer

Schmitt

Molfenter

Laureano

et al. 2019

Intl Journal of Cancer

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“…The intra-and intersubunit interactions between domains A and B are believed to be important for stabilizing the closed state of the channel. Disease mutations located in interfaces between domains A and B would weaken these interactions, thus facilitating channel opening (7)(8)(9)(10)(11)(12)(13)(14). Del-A would be expected to remove both intra-and intersubunit interactions between domains A and B, leading to destabilization of the closed state and channel activation.…”

Section: Discussionmentioning

confidence: 99%

“…The recently solved crystal structures of the NH 2 -terminal region of RyR have provided novel insights into the structural basis of disease mechanisms associated with the NH 2 -terminal mutations (7)(8)(9)(10)(11)(12)(13)(14). The three-dimensional structure of the NH 2 -terminal region of RyR contains three domains: domain A (residues 1-217), domain B (residues 218 -409), and domain C (residues 410 -543) (9).…”

Section: ؉mentioning

confidence: 99%

Roles of the NH2-terminal Domains of Cardiac Ryanodine Receptor in Ca2+ Release Activation and Termination

Liu

Sun

Xiao

et al. 2015

Journal of Biological Chemistry

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Background:The NH 2 -terminal region of cardiac ryanodine receptor (RyR2) contains three domains (A, B, and C) that harbor many disease-causing mutations. Results: Domains A, B, and C distinctively regulate the activation and termination of Ca 2ϩ release. Conclusion: Individual NH 2 -terminal domains play distinct roles in RyR2 channel function. Significance: These data shed new insights into the actions of RyR2 NH 2 -terminal disease mutations.

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“…The cap regulates the ability of the channel to open or close, turning RyRs into enormous allosteric membrane proteins 11 . A number of crystal structures have been reported, focusing mostly on the amino-terminal (N-terminal) three domains [12][13][14][15][16][17][18] , and a single domain containing a phosphorylation hot spot loop 19,20 .…”

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confidence: 99%

Crystal structures of wild type and disease mutant forms of the ryanodine receptor SPRY2 domain

Lau

Petegem

2014

Nat Commun

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Ryanodine receptors (RyRs) form channels responsible for the release of Ca 2 þ from the endoplasmic and sarcoplasmic reticulum. The SPRY2 domain in the skeletal muscle isoform (RyR1) has been proposed as a direct link with L-type calcium channels (Ca V 1.1), allowing for direct mechanical coupling between plasma membrane depolarization and Ca 2 þ release. Here we present the crystal structures of the SPRY2 domain from RyR1 and RyR2 at 1.34-1.84 Å resolution. They form two antiparallel b sheets establishing a core, and four additional modules of which several are required for proper folding. A buried disease mutation, linked to hypertrophic cardiomyopathy and loss-of-function, induces local misfolding and strong destabilization. Isothermal titration calorimetry experiments negate the RyR1 SPRY2 domain as the major link with Ca V 1.1. Instead, docking into full-length RyR1 cryo-electron microscopy maps suggests that the SPRY2 domain forms a link between the N-terminal gating ring and the clamp region.

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Type 2 Ryanodine Receptor Domain A Contains a Unique and Dynamic α-Helix That Transitions to a β-Strand in a Mutant Linked with a Heritable Cardiomyopathy

Cited by 38 publications

References 49 publications

Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer

Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer

Roles of the NH2-terminal Domains of Cardiac Ryanodine Receptor in Ca2+ Release Activation and Termination

Crystal structures of wild type and disease mutant forms of the ryanodine receptor SPRY2 domain

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