| Structural highlights
Function
RYR1_RABIT Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules. Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm. Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis (By similarity).[1] [2]
Publication Abstract from PubMed
Mutations 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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dulhunty AF, Laver DR, Gallant EM, Casarotto MG, Pace SM, Curtis S. Activation and inhibition of skeletal RyR channels by a part of the skeletal DHPR II-III loop: effects of DHPR Ser687 and FKBP12. Biophys J. 1999 Jul;77(1):189-203. PMID:10388749 doi:10.1016/S0006-3495(99)76881-5
- ↑ Kakizawa S, Yamazawa T, Chen Y, Ito A, Murayama T, Oyamada H, Kurebayashi N, Sato O, Watanabe M, Mori N, Oguchi K, Sakurai T, Takeshima H, Saito N, Iino M. Nitric oxide-induced calcium release via ryanodine receptors regulates neuronal function. EMBO J. 2011 Oct 28;31(2):417-28. doi: 10.1038/emboj.2011.386. PMID:22036948 doi:10.1038/emboj.2011.386
- ↑ Iyer KA, Hu Y, Nayak AR, Kurebayashi N, Murayama T, Samso M. Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM. Sci Adv. 2020 Jul 29;6(31):eabb2964. doi: 10.1126/sciadv.abb2964. eCollection, 2020 Jul. PMID:32832689 doi:http://dx.doi.org/10.1126/sciadv.abb2964
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