Structural dynamics underlying gating and regulation in IP3R channel

Inositol-1,4,5-trisphosphate receptors (IP3Rs) are activated by IP3 and Ca2+ and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IP3R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP3, Ca2+ and ATP in IP3R1, revealing conformational changes that couple ligand-binding to channel opening. Using a deep learning approach, we extracted dynamic properties of the key protein domains. From this, we find that IP3 binding relies upon intrinsic flexibility of the cytoplasmic ARM2 domain. Our results highlight a key role of dynamic side chains surrounding the ion conduction path in regulating gating behavior of IP3R channels. Altogether, this work defines a structural platform for mechanistic understanding of the molecular dynamics underlying ligand-binding, activation and regulation of the IP3R activity.

• Publication year

  2022

• Venue

  bioRxiv

• Publication date

  2022-05-28

• Fields of study

  Biology, Physics, Chemistry

• Identifiers
  DOI 10.1101/2022.05.27.493711
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Functional determination of calcium-binding sites required for the activation of inositol 1,4,5-trisphosphate receptors

  2022cited by this paper
• Highly accurate protein structure prediction with AlphaFold

  2021cited by this paper
• Cryo-EM structure of type 1 IP3R channel in a lipid bilayer

  2021cited by this paper
• Molecular structure of an open human KATP channel

  2021cited by this paper
• Structural basis for activation and gating of IP3 receptors

  2021cited by this paper
• Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist

  2020cited by this paper
• 3D Variability Analysis: Directly resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM images

  2020cited by this paper
• UCSF ChimeraX: Structure visualization for researchers, educators, and developers

  2020cited by this paper
• Structural Basis of Human KCNQ1 Modulation and Gating.

  2019cited by this paper
• New software tools in EMAN2 inspired by EMDatabank map challenge.

  2018cited by this paper
• Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures

  2018cited by this paper
• Structure of the CLC-1 chloride channel from Homo sapiens

  2018cited by this paper
• Inositol 1,4,5-trisphosphate Receptor Mutations associated with Human Disease.

  2018cited by this paper
• Structural basis for the regulation of inositol trisphosphate receptors by Ca2+ and IP3

  2018cited by this paper
• Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating

  2018cited by this paper
• Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH)

  2017cited by this paper
• MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy

  2017cited by this paper
• IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography

  2017cited by this paper
• Structure of IP3R channel: high-resolution insights from cryo-EM.

  2017cited by this paper
• IP3 receptor mutations and brain diseases in human and rodents

  2017cited by this paper
• Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia

  2017cited by this paper
• Unique Regulatory Properties of Heterotetrameric Inositol 1,4,5-Trisphosphate Receptors Revealed by Studying Concatenated Receptor Constructs*♦

  2016cited by this paper
• Inositol 1,4,5‐trisphosphate receptors and their protein partners as signalling hubs

  2016cited by this paper
• Defining the stoichiometry of inositol 1,4,5-trisphosphate binding required to initiate Ca2+ release

  2016cited by this paper
• Gctf: Real-time CTF determination and correction

  2015cited by this paper
• Gating machinery of InsP3R channels revealed by electron cryomicroscopy

  2015cited by this paper
• X-ray structure of the mammalian GIRK2-beta gamma G-protein complex.

  2013cited by this paper
• The Local Resolution of Cryo-EM Density Maps

  2013cited by this paper
• Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels*

  2013cited by this paper
• Structural basis for Ca2+ selectivity of a voltage-gated calcium channel

  2013cited by this paper
• Apo and InsP₃-bound crystal structures of the ligand-binding domain of an InsP₃ receptor.

  2012cited by this paper
• Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia

  2012cited by this paper
• RELION: Implementation of a Bayesian approach to cryo-EM structure determination

  2012cited by this paper
• Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2

  2011cited by this paper
• Role of Inositol 1,4,5-Trishosphate Receptors in Pathogenesis of Huntington’s Disease and Spinocerebellar Ataxias

  2011cited by this paper
• Flexible architecture of IP3R1 by Cryo-EM.

  2011cited by this paper
• Structural and functional conservation of key domains in InsP3 and ryanodine receptors

  2011cited by this paper
• LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery

  2011cited by this paper
• Regulation of IP(3)R Channel Gating by Ca(2+) and Ca(2+) Binding Proteins.

  2010cited by this paper
• On The Structural Basis of Modal Gating Behavior in K+ Channels

  2010cited by this paper
• Inositol trisphosphate receptor Ca2+ release channels in neurological diseases

  2010cited by this paper
• ATP Regulation of Type-1 Inositol 1,4,5-Trisphosphate Receptor Activity Does Not Require Walker A-type ATP-binding Motifs*

  2009cited by this paper
• The Type 2 Inositol (1,4,5)-Trisphosphate (InsP3) Receptor Determines the Sensitivity of InsP3-induced Ca2+ Release to ATP in Pancreatic Acinar Cells*

  2008cited by this paper
• Inositol trisphosphate receptor Ca2+ release channels.

  2007cited by this paper
• Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington's disease.

  2007cited by this paper
• Inference of macromolecular assemblies from crystalline state.

  2007cited by this paper
• Mode Switching Is the Major Mechanism of Ligand Regulation of InsP3 Receptor Calcium Release Channels

  2007cited by this paper
• Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor.

  2005cited by this paper
• Functional characterization of mammalian inositol 1,4,5-trisphosphate receptor isoforms.

  2005cited by this paper
• Calcium Regulation of Single Ryanodine Receptor Channel Gating Analyzed Using HMM/MCMC Statistical Methods

  2004cited by this paper
• Reaction mechanism determines NMDA receptor response to repetitive stimulation

  2004cited by this paper
• UCSF Chimera—A visualization system for exploratory research and analysis

  2004cited by this paper
• Structural insights into the regulatory mechanism of IP3 receptor.

  2004cited by this paper
• Deranged neuronal calcium signaling and Huntington disease.

  2004cited by this paper
• Novel Regulation of Calcium Inhibition of the Inositol 1,4,5-trisphosphate Receptor Calcium-release Channel

  2003cited by this paper
• Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy.

  2003cited by this paper
• Understanding the effects of concentration on the solvation structure of Ca2+ in aqueous solution I: the perspective on local structure from EXAFS and XANES

  2003cited by this paper
• Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand

  2002cited by this paper
• Functional characterization of the type 1 inositol 1,4,5-trisphosphate receptor coupling domain SII(+/-) splice variants and the Opisthotonos mutant form.

  2002cited by this paper
• Localization and function of a calmodulin-apocalmodulin-binding domain in the N-terminal part of the type 1 inositol 1,4,5-trisphosphate receptor.

  2002cited by this paper
• Atp Regulation of Recombinant Type 3 Inositol 1,4,5-Trisphosphate Receptor Gating

  2001cited by this paper
• Atp-Dependent Adenophostin Activation of Inositol 1,4,5-Trisphosphate Receptor Channel Gating

  2001cited by this paper
• Mapping of the ATP-binding Sites on Inositol 1,4,5-Trisphosphate Receptor Type 1 and Type 3 Homotetramers by Controlled Proteolysis and Photoaffinity Labeling*

  2001cited by this paper
• Ca(2+)-sensor region of IP(3) receptor controls intracellular Ca(2+) signaling.

  2001cited by this paper
• Ca2+‐sensor region of IP3 receptor controls intracellular Ca2+ signaling

  2001cited by this paper
• Regulation of the type III InsP(3) receptor by InsP(3) and ATP.

  2000cited by this paper
• ATP Regulation of Type 1 Inositol 1,4,5-Trisphosphate Receptor Channel Gating by Allosteric Tuning of Ca2+ Activation*

  1999cited by this paper
• Type 3 inositol trisphosphate receptors in RINm5F cells are biphasically regulated by cytosolic Ca2+ and mediate quantal Ca2+ mobilization.

  1999cited by this paper
• Modal gating transitions in cardiac ryanodine receptors during increases of Ca2+ concentration produced by photolysis of caged Ca2+

  1999cited by this paper
• Lateral inhibition of inositol 1,4,5-trisphosphate receptors by cytosolic Ca(2+).

  1999cited by this paper
• New developments in the molecular pharmacology of the myo-inositol 1,4,5-trisphosphate receptor.

  1998cited by this paper
• Inositol 1,4,5-tris-phosphate activation of inositol tris-phosphate receptor Ca2+ channel by ligand tuning of Ca2+ inhibition

  1998cited by this paper
• Single channel function of recombinant type-1 inositol 1,4,5-trisphosphate receptor ligand binding domain splice variants.

  1998cited by this paper
• Mode Switching Kinetics Produced by a Naturally Occurring Mutation in the Cytoplasmic Loop of the Human Acetylcholine Receptor ε Subunit

  1998cited by this paper
• Isoform-specific function of single inositol 1,4,5-trisphosphate receptor channels.

  1998cited by this paper
• Functional Consequences of Mutations of Conserved, Polar Amino Acids in Transmembrane Sequences of the Ca2+ Release Channel (Ryanodine Receptor) of Rabbit Skeletal Muscle Sarcoplasmic Reticulum*

  1998cited by this paper
• Cooperative activation of IP3 receptors by sequential binding of IP3 and Ca2+ safeguards against spontaneous activity.

  1997cited by this paper
• Inositol 1,4,5-Trisphosphate (InsP3) and Calcium Interact to Increase the Dynamic Range of InsP3 Receptor-dependent Calcium Signaling

  1997cited by this paper
• VMD: visual molecular dynamics.

  1996cited by this paper
• The inositol 1,4,5-trisphosphate receptor of cerebellum. Mn2+ permeability and regulation by cytosolic Mn2+

  1996cited by this paper
• Mutational Analysis of the Ligand Binding Site of the Inositol 1,4,5-Trisphosphate Receptor*

  1996cited by this paper
• High Ca2+ concentrations induce a low activity mode and reveal Ca2(+)‐independent long shut intervals in BK channels from rat muscle.

  1996cited by this paper
• Deoxygenated inositol 1,4,5-trisphosphate analogues and their interaction with metabolic enzymes. (1R,2R,4R)-cyclohexane-1,2,4-tris(methylenesulfonate): a potent selective 5-phosphatase inhibitor.

  1993cited by this paper
• ATP modulates the function of inositol 1,4,5-trisphosphate-gated channels at two sites.

  1993cited by this paper
• The pore dimensions of gramicidin A.

  1993cited by this paper
• Structural and functional characterization of inositol 1,4,5-trisphosphate receptor channel from mouse cerebellum.

  1991cited by this paper
• Bell-shaped calcium-response curves of lns(l,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum

  1991cited by this paper
• A cerebellar Purkinje cell marker P400 protein is an inositol 1,4,5‐trisphosphate (InsP3) receptor protein. Purification and characterization of InsP3 receptor complex.

  1990cited by this paper
• Calcium flux mediated by purified inositol 1,4,5-trisphosphate receptor in reconstituted lipid vesicles is allosterically regulated by adenine nucleotides.

  1990cited by this paper
• Solubilization, purification, and characterization of an inositol trisphosphate receptor.

  1988cited by this paper
• Predicted nucleotide-binding properties of p21 protein and its cancer-associated variant

  1983cited by this paper

• Functional determination of calcium-binding sites required for the activation of inositol 1,4,5-trisphosphate receptors

  2022influential citation