Molecular Changes in the Cardiac RyR2 With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Figures

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  FIGURE 1. Distribution on RyR2 structure of gain-of-function RyR2 CPVT mutations and changes in RyR2 pore with channel opening, likely to characterize the pore with CPVT. (A) A side view of RyR2 as viewed in its location between the transverse (T) – tubule and SR membranes. Three of the four RyR monomers forming the tetrameric channel are shown, with the various domains of the central monomer are color coded. The fourth monomer is hidden behind the three monomers. (B) A cytosolic section through the tetramer perpendicular to the view in (A) and parallel to the T-tubule membrane. In (A,B), 108 human gain-of-function mutations (Priori et al., 2021) are shown as red spheres. Color codes for domains in (a) and (b) are given along with residue numbers. HD – helical domain. The figure has been modified from Figure 4 (Priori et al., 2021) under copyright License #5194490720614. Labeling only has been modified. (C) The pore is shown traversing the SR membrane. In the closed conformation (left) the pore is constricted to ∼1 Å at I4868. In the open conformation the constriction expands to ∼3.6 Å with the minimum at Q4864. There is a second constriction at the selectivity filter (SF) near the…

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  FIGURE 2. Structural changes associated with RyR mutations. (A) CryoEM images showing that the R615C mutation induces RyR1 channel opening by disrupting interactions between the Nsol and Bsol regions. (i,ii) show local changes around R615 as a result of the mutation, while (iii,iv) illustrate the resulting global changes in the protein. Alpha helices are represented as cylinders. (i) WT (colored) and R615C (gray) structures are superimposed, based on the Nsol region. The location of residue 615 is shown at the junction between the three solenoid regions, the N-terminal solenoid (Nsol, residues 395–630, containing Arg615), junctional solenoid (JSol, residues 1657–2145) and bridging solenoid (Bsol, residues 2146–3613). NTD-A and NTD-B are N-terminal disease hot spot regions. The lower heavy yellow arrow indicates the 10 Å movement of Bsol in the vicinity of residue 2457 resulting from the R615C mutation. This region of Bsol contacts the Nterminal domain A (NTD-A’) of a neighboring subunit. Therefore, as a result of the relative movement of Bsol, the hotspot regions NTD-A and NTD-B no longer form intersubunit interactions, the gap between the N-terminal domains of two neighboring subunits…