Structure and Function of the Human Ryanodine Receptors and Their Association with Myopathies—Present State, Challenges, and Perspectives

Figures

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  Figure 1. Schematics of the human RyR1 (a) and RyR2 (b) sequences showing the domain organization and the approximate locations of several disease-causing mutations. The individual subdomains of the N-Terminal Domain (NTD) are indicated. Δex3 refers to the CPVT1-associated deletion of exon 3. The SPRY domains are comprised from more than one region of the sequence, hence their multiple sequence ranges. Adapted from Bauerová-Hlinková et al. [103].

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  Figure 2. Two representations of the RyR1 tetramer. Top: The solvent-accessible surface area allows the large-scale structures originally identified by cryo-EM to be distinguished. Bottom: A ribbon diagram showing which domains correspond to the individual large-scale structures. The views to the right are rotated 90° about the horizontal axis. The individual domains are colored as in Figure 1 and Figure 3. The structure is the 3.8 Å RyR1 structure (PDB ID 3j8h) from Yan et al. [11]. This structure was chosen to illustrate the structural features of the ryanodine receptors because it has the highest resolution and completeness (part of the long helical domain is lacking in the available RyR2 structures).

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  Figure 3. The RyR1 monomer from Yan et al. [11]. Two perpendicular α-solenoids can be distinguished. α-solenoid 1 runs top-to-bottom and includes NTD:C, part of the handle domain, and the central domain. α-solenoid 2 runs left-to-right and includes part of the handle domain and the long, curved helical domain. The SPRY domains and Repeat1–2 are attached to the periphery of solenoid 1, while the phosphorylation target domain Repeat3–4 sits atop solenoid 2. The domains are colored as follows: the NTD is green, the SPRY domains are gray (SPRY1 is light gray, SPRY2 is middle gray, SPRY3 is dark gray), Repeat1–2 is darker orange, the handle domain is magenta, the two halves of the helical domain are cyan, Repeat3–4 is lighter orange, the central domain is red, and the transmembrane channel domain is purple. The central domain of RyR1 includes a calcium-binding EF-hand motif which is colored yellow.

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  Figure 4. The O-ring and U-motif of the RyR1 structure from Yan et al. [11]. The U-motif from the central domain is colored a brighter red than the rest of the central domain. The parts of the O-motif are colored as follows: the cytosolic part of the S6 α-helix from the TM domain is sand-colored, the voltage-sensor-like motif is colored cyan, and the C-terminal zinc-finger domain is colored blue (the residues of the zinc-finger themselves are colored green and shown as sticks).

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  Figure 5. The N-terminal domain of human RyR2 from Borko et al. [157] (PDB ID 4jkq). The individual subdomains are colored blue (domain A), green (domain B), and yellow (domain C). The “central helix” is colored orange. The locations of individual disease-causing mutations are shown as sticks. Note that they are grouped in three distinct places: on the surfaces of domains A and B and on the central helix. The long, disordered loop containing residues 98–107 is not visible in this structure.

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  Figure 6. Four representative structures of the individual RyR domain crystal structures described in the text. Domains from the RyR2 isoform are shown except for Repeat1–2, where only the RyR1 structure is known. (a) The RyR2 SPRY1 domain (PDB ID 5c33 [162]). The β-sheet extensions present in the full-length structure but missing in the SPRY1 crystal structure are shown in pink. The “finger” motif is colored orange, while the conformation of the loop comprising the finger domain in the complete structure is colored purple. Residues of which mutations are associated with diseases in RyR2 are shown as sticks. (b) The RyR2 SPRY2 domain (PDB ID 4p9i [163]). Coloring is as in (a). In (a,b), the extensions were placed by superimposing the given structure on the closed form of the full-length RyR2 cryo-EM structure (5go9 [148]). (c) The RyR1 Repeat1–2 domain (PDB ID 5c30 [162]). The U-lid of this domain is colored cyan. To make it easy to distinguish the two repeats, Repeat 2 is colored a lighter shade than Repeat 1. (d) The RyR2 Repeat3–4 domain (PDB ID 4etv [164]). The coloring is as in (c). The beginning and end of the phosphorylation loop, most of which is not visible, are colored orange.