title: Common allosteric mechanisms between ryanodine and inositol-1,4,5-trisphosphate receptors.
abstract: Ryanodine receptors (RyRs) are calcium release channels found in the membrane of the endoplasmic reticulum (ER). We recently described the crystal structure of the RyR1 N-terminal disease hot spot. It is built up by three domains that show clear structural homology with the inositol-1,4,5-triphosphate (IP3) binding core and suppressor domain of IP3 receptors (IP3Rs) . Here we analyze the structural features of the domains in both calcium release channels, and propose a model for the closed state of the IP3R N-terminal region. This model explains the effect of the suppressor domain on the affinity for IP3 and is supported by mutational studies performed previously. We propose a mechanism whereby opening of both RyR and IP3R is allosterically coupled to a displacement of the N-terminal domain from the following two domains. This displacement can be affected by disease mutations, glutathionylation of a highly reactive cysteine residue, or ligand binding.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Yuchi
authors.forename: Filip
authors.initials: F
authors.lastname: Van Petegem
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D003545:Cysteine / Q000737:chemistry; D004252:DNA Mutational Analysis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry*; D008024:Ligands; D051379:Mice; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D019837:Ryanodine Receptor Calcium Release Channel; D015544:Inositol 1,4,5-Trisphosphate; D003545:Cysteine