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- PDB-7ocd: Resting state GluA1/A2 heterotetramer in complex with auxiliary s... -

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Basic information

Entry
Database: PDB / ID: 7ocd
TitleResting state GluA1/A2 heterotetramer in complex with auxiliary subunit TARP gamma 8 (LBD-TMD)
Components
  • Glutamate receptor 2
  • Isoform Flip of Glutamate receptor 1
  • Voltage-dependent calcium channel gamma-8 subunit
KeywordsMEMBRANE PROTEIN / AMPAR / ion channels / neurotransmission
Function / homology
Function and homology information


Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / axonal spine / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / COPII-mediated vesicle transport / cellular response to ammonium ion / response to sucrose / L-type voltage-gated calcium channel complex ...Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / axonal spine / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / COPII-mediated vesicle transport / cellular response to ammonium ion / response to sucrose / L-type voltage-gated calcium channel complex / neuron spine / myosin V binding / postsynaptic neurotransmitter receptor diffusion trapping / proximal dendrite / regulation of monoatomic ion transmembrane transport / regulation of AMPA receptor activity / channel regulator activity / Trafficking of AMPA receptors / LGI-ADAM interactions / protein phosphatase 2B binding / response to arsenic-containing substance / cellular response to L-glutamate / cellular response to dsRNA / dendritic spine membrane / long-term synaptic depression / beta-2 adrenergic receptor binding / Synaptic adhesion-like molecules / cellular response to peptide hormone stimulus / response to morphine / neuronal cell body membrane / spine synapse / dendritic spine neck / protein kinase A binding / dendritic spine head / peptide hormone receptor binding / cellular response to amine stimulus / response to psychosocial stress / spinal cord development / perisynaptic space / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / AMPA glutamate receptor activity / transmission of nerve impulse / response to lithium ion / Trafficking of GluR2-containing AMPA receptors / behavioral response to pain / kainate selective glutamate receptor activity / AMPA glutamate receptor complex / cellular response to glycine / adenylate cyclase binding / extracellularly glutamate-gated ion channel activity / immunoglobulin binding / asymmetric synapse / ionotropic glutamate receptor complex / conditioned place preference / excitatory synapse / response to electrical stimulus / regulation of receptor recycling / G-protein alpha-subunit binding / glutamate receptor binding / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of excitatory postsynaptic potential / long-term memory / positive regulation of synaptic transmission / positive regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / regulation of postsynaptic membrane neurotransmitter receptor levels / regulation of synaptic transmission, glutamatergic / neuronal action potential / voltage-gated calcium channel activity / response to fungicide / cytoskeletal protein binding / glutamate-gated receptor activity / synapse assembly / regulation of long-term synaptic depression / extracellular ligand-gated monoatomic ion channel activity / cellular response to brain-derived neurotrophic factor stimulus / presynaptic active zone membrane / glutamate-gated calcium ion channel activity / somatodendritic compartment / dendrite membrane / ionotropic glutamate receptor binding / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / synaptic membrane / dendritic shaft / SNARE binding / response to cocaine / calcium channel regulator activity / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / PDZ domain binding / protein tetramerization / cellular response to amino acid stimulus / neuromuscular junction / response to nutrient levels / establishment of protein localization / response to peptide hormone / postsynaptic density membrane
Similarity search - Function
Voltage-dependent calcium channel, gamma-8 subunit / Butyryl-CoA Dehydrogenase, subunit A; domain 3 - #150 / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain ...Voltage-dependent calcium channel, gamma-8 subunit / Butyryl-CoA Dehydrogenase, subunit A; domain 3 - #150 / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-E2Q / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Glutamate receptor 1 / Glutamate receptor 2 / Voltage-dependent calcium channel gamma-8 subunit
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsZhang, D. / Watson, J.F. / Matthews, P.M. / Cais, O. / Greger, I.H.
Funding support2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_U105174197
Biotechnology and Biological Sciences Research Council (BBSRC)BB/N002113/1
CitationJournal: Nature / Year: 2021
Title: Gating and modulation of a hetero-octameric AMPA glutamate receptor.
Authors: Danyang Zhang / Jake F Watson / Peter M Matthews / Ondrej Cais / Ingo H Greger /
Abstract: AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning. A diverse array of AMPAR signalling complexes are ...AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength. However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1-GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties.
History
DepositionApr 26, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 9, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 16, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 30, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Isoform Flip of Glutamate receptor 1
C: Isoform Flip of Glutamate receptor 1
D: Glutamate receptor 2
I: Voltage-dependent calcium channel gamma-8 subunit
J: Voltage-dependent calcium channel gamma-8 subunit
B: Glutamate receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)491,05616
Polymers484,9706
Non-polymers6,08610
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area27620 Å2
ΔGint-270 kcal/mol
Surface area80970 Å2

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Components

#1: Protein Isoform Flip of Glutamate receptor 1 / GluR-1 / AMPA-selective glutamate receptor 1 / GluR-A / GluR-K1 / Glutamate receptor ionotropic / ...GluR-1 / AMPA-selective glutamate receptor 1 / GluR-A / GluR-K1 / Glutamate receptor ionotropic / AMPA 1 / GluA1


Mass: 102661.930 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gria1, Glur1 / Production host: Homo sapiens (human) / References: UniProt: P19490
#2: Protein Glutamate receptor 2


Mass: 96247.055 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Homo sapiens (human) / References: UniProt: P19491
#3: Protein Voltage-dependent calcium channel gamma-8 subunit / Neuronal voltage-gated calcium channel gamma-8 subunit / Transmembrane AMPAR regulatory protein ...Neuronal voltage-gated calcium channel gamma-8 subunit / Transmembrane AMPAR regulatory protein gamma-8 / TARP gamma-8


Mass: 43576.004 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Cacng8 / Production host: Homo sapiens (human) / References: UniProt: Q8VHW5
#4: Chemical
ChemComp-E2Q / 6-nitro-2,3-bis(oxidanylidene)-1,4-dihydrobenzo[f]quinoxaline-7-sulfonamide


Mass: 336.280 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H8N4O6S
#5: Chemical
ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


Mass: 790.145 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: GluA1/A2 heterotetramer in complex with auxiliary subunit TARP gamma 8
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Purified protein was incubated with 100 uM NBQX for at least 30 min on ice before freezing.
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
4GctfCTF correction
7UCSF Chimeramodel fitting
9PHENIXmodel refinement
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105471 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 6QKC

6qkc


Accession code: 6QKC / Source name: PDB / Type: experimental model

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