Biotechnology and Biological Sciences Research Council (BBSRC)
BB/N002113/1
United Kingdom
Spanish Ministry of Science, Innovation, and Universities
PID2019-106284GA-I00
United Kingdom
Citation
Journal: Nat Commun / Year: 2022 Title: Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor. Authors: Beatriz Herguedas / Bianka K Kohegyi / Jan-Niklas Dohrke / Jake F Watson / Danyang Zhang / Hinze Ho / Saher A Shaikh / Remigijus Lape / James M Krieger / Ingo H Greger / Abstract: AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor's ligand-binding domains (LBDs) leads to ion channel ...AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor's ligand-binding domains (LBDs) leads to ion channel activation and desensitization. Gating kinetics shape synaptic transmission and are strongly modulated by transmembrane AMPAR regulatory proteins (TARPs) through currently incompletely resolved mechanisms. Here, electron cryo-microscopy structures of the GluA1/2 TARP-γ8 complex, in both open and desensitized states (at 3.5 Å), reveal state-selective engagement of the LBDs by the large TARP-γ8 loop ('β1'), elucidating how this TARP stabilizes specific gating states. We further show how TARPs alter channel rectification, by interacting with the pore helix of the selectivity filter. Lastly, we reveal that the Q/R-editing site couples the channel constriction at the filter entrance to the gate, and forms the major cation binding site in the conduction path. Our results provide a mechanistic framework of how TARPs modulate AMPAR gating and conductance.
History
Deposition
Dec 12, 2021
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Header (metadata) release
Feb 23, 2022
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Map release
Feb 23, 2022
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Update
Dec 13, 2023
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Current status
Dec 13, 2023
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Entire : Complex between GluA1/2 AMPA receptor and auxiliary subunit TARP ...
Entire
Name: Complex between GluA1/2 AMPA receptor and auxiliary subunit TARP gamma8
Components
Complex: Complex between GluA1/2 AMPA receptor and auxiliary subunit TARP gamma8
Protein or peptide: GluA1 AMPA glutamate receptor 1, Flip isoform
Protein or peptide: AMPA Glutamate Receptor 2, flip isoform, Q/R edited
Protein or peptide: TARP-gamma 8
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Supramolecule #1: Complex between GluA1/2 AMPA receptor and auxiliary subunit TARP ...
Supramolecule
Name: Complex between GluA1/2 AMPA receptor and auxiliary subunit TARP gamma8 type: complex / ID: 1 / Parent: 0 / Macromolecule list: all Details: GluA2 and TARP8 are expressed as a tandem construct
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: 3-4 second blots.
Details
Sample was incubated with 87 uM CTZ for 30 minutes and 100 mM L-Glutamate was added before grid preparation
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Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 9664 / Average exposure time: 4.0 sec. / Average electron dose: 51.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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