title: Gating machinery of InsP3R channels revealed by electron cryomicroscopy.
abstract: Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca(2+) signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP3Rs, a mechanistic understanding of their structure-function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 Å) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP3R channel in its apo-state. At this resolution, we are able to trace unambiguously ∼85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca(2+)-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed α-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.
authors.affiliation: Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, Texas 77030, USA.
authors.forename: Guizhen
authors.initials: G
authors.lastname: Fan
authors.affiliation: National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Baker
authors.affiliation: National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, Texas 77030, USA.
authors.forename: Mariah R
authors.initials: MR
authors.lastname: Baker
authors.affiliation: Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, Texas 77030, USA.
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Sinyagovskiy
authors.affiliation: National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
authors.affiliation: National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ludtke
authors.affiliation: Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, Texas 77030, USA.
authors.forename: Irina I
authors.initials: II
authors.lastname: Serysheva
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D020285:Cryoelectron Microscopy; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D015640:Ion Channel Gating; D008958:Models, Molecular; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000378:metabolism
chemical_list: D001059:Apoproteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D021122:Protein Subunits; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium