Three-dimensional perspective on ryanodine receptor mutations causing skeletal and cardiac muscle-related diseases

Ryanodine receptors (RyRs) are large intracellular calcium channels with a well-documented role in excitation-contraction coupling in skeletal and cardiac muscles, which have their dedicated isoforms RyR1 and RyR2, respectively [1,2]. Identified around 1983 in the context of sarcoplasmic reticulum (SR)-T tubule junctions [3], RyR was first purified in 1987–1988 [4, 5, 6] and cloned soon thereafter [7,8]. RyRs are notoriously complex proteins due to their large size (2.2 MDa) and having numerous binding partners. Named for its ability to bind the plant alkaloid, ryanodine [9, 10, 11], the function of this ion channel has been characterized extensively (in vivo studies, live-cell Ca2+ imaging, single channel, radioligand binding). However, for the longest time there was little to no information on the three-dimensional (3D) structure of RyRs resulting from the inability to crystallize such a large protein. Advancements in cryo-electron microscopy (cryo-EM) allowed detailed structural elucidation [12, 13, 14, 15∗]. In this review we discuss mutations in RyR1 and RyR2 from a structural perspective and highlight few mutations studied in greater structural detail. Given the space limitations the bibliographic references were reduced to a minimum, but we want to highlight the supplementary tables, with >250 known mutations of RyR1 and >200 known mutations of RyR2 and their corresponding references. Throughout the text, the residue numbering refers to the species in the referenced article.

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