Inositol-1,4,5-trisphosphate receptors (InsP3Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca2+ channels1. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP3R gating is initiated by InsP3 binding to the InsP3-binding core (IBC, residues 224–604 of InsP3R1)2 and it requires the suppressor domain (SD, residues 1–223 of InsP3R1)2,3,4,5,6,7,8. Here we present structures of the amino-terminal region (NT, residues 1–604) of rat InsP3R1 with (3.6 Å) and without (3.0 Å) InsP3 bound. The arrangement of the three NT domains, SD, IBC-β and IBC-α, identifies two discrete interfaces (α and β) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP3R10 and of the ABC domains docked into RyR9 are remarkably similar. The importance of the α-interface for activation of InsP3R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations9,11,12. Binding of InsP3 causes partial closure of the clam-like IBC, disrupting the β-interface and pulling the SD towards the IBC. This reorients an exposed SD loop (‘hotspot’ (HS) loop) that is essential for InsP3R activation7. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease9,11,12. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP3R, and an InsP3R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP3 and blocked by ryanodine. Activation mechanisms are conserved between InsP3R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-β or B domain), to gate the pore.
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We thank P. Allen and D. MacLennan for gifts of plasmids encoding RyR2 and RyR1, respectively. C.W.T. thanks T. Rahman and V. Konieczny for discussions. M.I. acknowledges K. Mikoshiba and T. Michikawa for long-standing support and discussions. This work was supported by grants from the Heart and Stroke Foundation of Ontario (T-7181) to M.I., National Institutes of Health Research (EY012347 and NS059969) to J.B.A., the Wellcome Trust (085295), the Biotechnology and Biological Sciences Research Council (BB/H009736) and the Medical Research Council (G0900049) to C.W.T. M.-D.S. is supported by postdoctoral fellowships from the Canadian Institutes of Health Research and the National Research Foundation of Korea (2009-352-E00006). A.M.R. is a fellow of Queens’ College, Cambridge. M.I. holds a Canadian Research Chair in Cancer Structural Biology.
This file contains a Supplementary Discussion, Supplementary References, Supplementary Tables 1-9 and Supplementary Figures 1-11 with legends.
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Current Opinion in Cell Biology (2019)