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- W2318548871 abstract "The contraction of both cardiac and skeletal muscle requires the rapid release of calcium ions from the endoplasmic or sarcoplasmic reticulum. The release is governed by Ryanodine Receptors (RyRs), large ion channels selective for calcium. Over 200 mutations in RyRs have been associated with severe genetic diseases, including CPVT and ARVD2, which cause triggered cardiac arrhythmias. Here we present a high-resolution (2.5 Angstrom) crystal structure of an entire disease hot spot of the ryanodine receptor, harboring 57 different disease mutations. For the first time, we can now look at the effect of disease mutations on the structure and stability of the protein, and derive a mechanism by which the mutations cause a faulty channel. The mutations destabilize functional domain-domain interactions. These interactions normally act as a 'brake' on the channel, preventing opening under resting conditions. Weakening the domain interfaces causes a leak of calcium ions into the cytoplasm, resulting in delayed after depolarizations (DADs) due to increased activity of the sodium-calcium exchanger. The high resolution structure, combined with low resolution electron microscopy reconstructions, now provides a molecular template for the development of novel drugs that can stabilize the domain-domain interactions. Heart and Stroke Foundation of Canada" @default.
- W2318548871 created "2016-06-24" @default.
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- W2318548871 date "2011-09-01" @default.
- W2318548871 modified "2023-09-27" @default.
- W2318548871 title "258 Cardiac arrhythmias: Insights into CPVT and ARVD2 through the crystal structure of the ryanodine receptor N-terminal disease hot spot" @default.
- W2318548871 doi "https://doi.org/10.1016/j.cjca.2011.07.190" @default.
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