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Cryo-EM structure of recombinant mouse Ryanodine Receptor type 2 wild type in complex with FKBP12.6
Structural highlights
FunctionRYR2_MOUSE Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.[1] [2] [3] [4] Publication Abstract from PubMedMutations in ryanodine receptors (RyRs), intracellular Ca(2+) channels, are associated with deadly disorders. Despite abundant functional studies, the molecular mechanism of RyR malfunction remains elusive. We studied two single-point mutations at an equivalent site in the skeletal (RyR1 R164C) and cardiac (RyR2 R176Q) isoforms using ryanodine binding, Ca(2+) imaging, and cryo-electron microscopy (cryo-EM) of the full-length protein. Loss of the positive charge had greater effect on the skeletal isoform, mediated via distortion of a salt bridge network, a molecular latch inducing rotation of a cytoplasmic domain, and partial progression to open-state traits of the large cytoplasmic assembly accompanied by alteration of the Ca(2+) binding site, which concur with the major "hyperactive" feature of the mutated channel. Our cryo-EM studies demonstrated the allosteric effect of a mutation situated ~85 A away from the pore and identified an isoform-specific structural effect. Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM.,Iyer KA, Hu Y, Nayak AR, Kurebayashi N, Murayama T, Samso M Sci Adv. 2020 Jul 29;6(31):eabb2964. doi: 10.1126/sciadv.abb2964. eCollection , 2020 Jul. PMID:32832689[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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