Structural and functional conservation of key domains in InsP3 and ryanodine receptors

• Published in: Nature (London) 2012-01, Vol.483 (7387), p.108-112
• Main Authors: Seo, Min-Duk, Velamakanni, Saroj, Ishiyama, Noboru, Stathopulos, Peter B., Rossi, Ana M., Khan, Samir A., Dale, Philippa, Li, Congmin, Ames, James B., Ikura, Mitsuhiko, Taylor, Colin W.
• Format: Article
• Language: English
• Subjects: 631/45/535; 631/57; Amino Acid Sequence; Animals; Apoproteins - chemistry; Apoproteins - metabolism; Biological and medical sciences; Cryoelectron Microscopy; Crystalline structure; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Inositol 1,4,5-Trisphosphate - chemistry; Inositol 1,4,5-Trisphosphate - metabolism; Inositol 1,4,5-Trisphosphate Receptors - chemistry; Inositol 1,4,5-Trisphosphate Receptors - genetics; Inositol 1,4,5-Trisphosphate Receptors - metabolism; letter; Models, Molecular; Molecular biophysics; Molecular Sequence Data; multidisciplinary; Mutagenesis; Protein Conformation; Protein Structure, Tertiary; Rabbits; Rats; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Ryanodine Receptor Calcium Release Channel - chemistry; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; Science; Science (multidisciplinary); Structure in molecular biology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10751

Structures of the amino-terminal region of inositol-1,4,5-trisphosphate receptor 1 with and without InsP 3 bound reveal two discrete interfaces between the InsP 3 -binding core and suppressor domain that are similar to and functionally interchangeable with those in the equivalent domains of ryanodine receptor 1. Control of calcium channels Almost all known responses to the stimuli that evoke Ca 2+ release from intracellular stores are mediated by two families of intracellular Ca 2+ channels: inositol-1,4,5-trisphosphate receptors (InsP 3 Rs) and ryanodine receptors (RyRs). The structures of the amino-terminal region of InsP 3 R1 have now been determined with and without IP 3 bound. Two discrete inter-domain interfaces are present, a feature also seen in a previously published structure of RyR1. The physiological importance of one of these interfaces was confirmed by mutagenesis. This work has implications for the study of known disease-causing mutations in ryanodine receptors. Inositol-1,4,5-trisphosphate receptors (InsP 3 Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca 2+ channels 1 . 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. InsP 3 R gating is initiated by InsP 3 binding to the InsP 3 -binding core (IBC, residues 224–604 of InsP 3 R1) 2 and it requires the suppressor domain (SD, residues 1–223 of InsP 3 R1) 2 , 3 , 4 , 5 , 6 , 7 , 8 . Here we present structures of the amino-terminal region (NT, residues 1–604) of rat InsP 3 R1 with (3.6 Å) and without (3.0 Å) InsP 3 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 InsP 3 R 10 and of the ABC domains docked into RyR 9 are remarkably similar. The importance of the α-interface for activation of InsP 3 R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations 9 , 11 , 12 . Binding of InsP 3 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 InsP 3 R activation 7 . The loop is conserved in RyR and includes mutations that are associated with malignant hyp