Journal
COMMUNICATIONS BIOLOGY
Volume 1, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-018-0103-x
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Funding
- Japan Society for the Promotion of Sciences KAKENHI [JP16K08507, JP16H04748, JP15K08243]
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) [JP17am0101080j0001]
- Practical Research Project for Rare/Intractable Diseases [JP17ek0109202h0001]
- Japan Agency for Medical Research and Development (AMED)
- Intramural Research Grant [29-4]
- Vehicle Racing Commemorative Foundation
- Institute of Seizon Life Sciences
- Institute for Environmental & Gender-specific Medicine, Juntendo University
- Ministry of Education, Culture, and Sports, Science and Technology, Japan
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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.
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