Editors' ChoiceStructural Biology

New connections: How to become more flexible and open up

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Sci. Signal.  23 May 2017:
Vol. 10, Issue 480, eaan7911
DOI: 10.1126/scisignal.aan7911

Cryo-EM–generated structures provide insight into how RyR2 is gated and how phosphorylation may affect the activation process.

The type 2 ryanodine receptors (RyR2s) are large, tetrameric channels that mediate Ca2+ release from the sarcoplasmic reticulum of cardiomyocytes to initiate cardiac muscle contraction. Mutations in this intracellular Ca2+ channel are associated with various cardiac diseases that may lead to heart failure. Dhindwal et al. used cryo–electron microscopy (cryo-EM) to determine the structure of rabbit RyR2 in complex with the regulatory protein FKBP12.6 in the closed state at 11.8 Å resolution. They found two conformations of RyR2, which may correspond to the extent of phosphorylation of a domain that harbors several disease-associated mutations. Because the more flexible conformation may correspond to phosphorylated RyR2, the authors suggest that phosphorylation may reduce the energy required for the Ca2+ channel to transition to an open state. Peng et al. also used cryo-EM to determine the structure of porcine RyR2 in both the closed state (at a resolution of 4.4 Å) and in the open state (at a resolution of 4.2 Å). Comparison of these structures uncovered the position shifts of the various domains of RyR2 that lead to conformational changes in the central domain that open or close the channel. Together, these results provide a structural basis for understanding the potential effect of phosphorylation on the activation of RyR2 and the gating of this Ca2+ channel.

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