CPVT-associated mutation loci in a RyR2 channel molecule. (A) Alignment of the sequences around S4–5 linker of RyR orthologues. Letters h, m, r, f, and Dm represent human, mouse, rabbit, frog, and D. melanogaster (fruit fly), respectively. (B) The mutation locus of K4750Q in a homology model of the RyR2 channel domain. (left) View of tetramers parallel to the plane of the lipid bilayer membrane. (right) View of tetramers from the cytosol. Magenta balls, K4750 residues; reddish brown ribbons, S6 segments (helices); yellowish green ribbons, S5 segments (helices); red ball, Ca²⁺. (C) The mutation sites of R2473S and K4750Q in the full-length RyR2 depicted by the letters R and K, respectively. Zipper domains, I domain, and EF hands for the putative Ca²⁺ binding sites are also illustrated.