LAUSR

Significance Skeletal muscle contraction is governed by ryanodine receptor 1 (RyR1) channels. Ryanodine receptors (RyRs) are the largest ion channels known, with multiple interconnected regulatory domains. Single point mutations of RyRs cause life-threatening diseases, and understanding their underlying molecular mechanism requires interpretation within the full protein context. Our cryo-EM reconstructions of the severe RyR1 Y523S mutation (in rabbit; corresponding to human Y522S) under open and closed states reveal widespread and far-reaching conformational changes transmitted over multiple domains that result in preactivation of the channel and suggest altered communication with RyR1’s partner protein, the dihydropyridine receptor. The mutation reveals correlations between distinctive structural traits and functional anomalies and provides insight into the future design of therapies to modulate RyRs.