Structural characterization of MH/CCD NTD mutations in skeletal ryanodine receptor by cryo-EM

Abstract

Single-point mutations in the skeletal isoform of ryanodine receptors (RyR1s) are linked to debilitating and even deadly disorders such as central core disease and malignant hyperthermia. Most such mutations result in a constitutive leak of Ca2+ from the endoplasmic reticulum into the cytoplasm and while functional data exists, knowledge about the structural effects remain scant. We performed cryo-electron microscopy (cryo-EM) on full-length mutants of RyR1 protein expressed in HEK293 cells and elucidated the underlying molecular mechanism.