Journal
NATURE
Volume 572, Issue 7769, Pages 347-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1377-y
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Funding
- National Key R&D Program from Ministry of Science and Technology of China [2016YFA0500402]
- National Key Basic Research (973) Program from Ministry of Science and Technology of China [2015CB910101]
- National Natural Science Foundation of China [31621092, 31630017, 81861138009]
- Shirley M. Tilghman endowed professorship from Princeton University
- Heart and Stroke Foundation of Canada
- Canadian Institutes of Health Research
- Heart and Stroke Foundation Chair in Cardiovascular Research
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The high-conductance intracellular calcium (Ca2+) channel RyR2 is essential for the coupling of excitation and contraction in cardiac muscle. Among various modulators, calmodulin (CaM) regulates RyR2 in a Ca2+-dependent manner. Here we reveal the regulatory mechanism by which porcine RyR2 is modulated by human CaM through the structural determination of RyR2 under eight conditions. Apo-CaM and Ca2+-CaM bind to distinct but overlapping sites in an elongated cleft formed by the handle, helical and central domains. The shift in CaM-binding sites on RyR2 is controlled by Ca2+ binding to CaM, rather than to RyR2. Ca2+-CaM induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95 and Ca2+-activated channel. By contrast, the pore of the ATP, caffeine and Ca2+-activated channel remains open in the presence of Ca2+-CaM, which suggests that Ca2+-CaM is one of the many competing modulators of RyR2 gating.
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