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- Title
A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca<sup>2+</sup> sensitivity.
- Authors
Murayama, Takashi; Ogawa, Haruo; Kurebayashi, Nagomi; Ohno, Seiko; Horie, Minoru; Sakurai, Takashi
- Abstract
Ryanodine receptors (RyRs) are Ca2+ release channels in the sarcoplasmic reticulum of skeletal and cardiac muscles and are essential for muscle contraction. Mutations in genes encoding RyRs cause various muscle and arrhythmogenic heart diseases. Although RyR channels are activated by Ca2+, the actual mechanism of Ca2+ binding remains largely unknown. Here, we report the molecular basis of Ca2+ binding to RyRs for channel activation and discuss its implications in disease states. RyR1 and RyR2 carrying mutations in putative Ca2+ and caffeine-binding sites were functionally analysed. The results were interpreted with respect to recent near-atomic resolution RyR1 structures in various ligand states. We demonstrate that a tryptophan residue in the caffeine-binding site controls the structure of the Ca2+-binding site to regulate the Ca2+ sensitivity. Our results reveal the initial step of RyR channel activation by Ca2+ and explain the molecular mechanism of Ca2+ sensitization by caffeine and disease-causing mutations. Takashi Murayama et al. report the molecular basis of calcium binding to ryanodine receptors, a process essential for muscle contraction. They find that a tryptophan residue in the caffeine binding site controls the structure of the calcium binding site, affecting calcium sensitivity.
- Subjects
RYANODINE receptors; TRYPTOPHAN; CALCIUM ions; SARCOPLASMIC reticulum; GENETIC mutation; MYOCARDIUM; MUSCLE contraction
- Publication
Communications Biology, 2018, Vol 1, Issue 1, pN.PAG
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-018-0103-x