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dc.contributor.authorHerguedas, Beatriz
dc.contributor.authorKohegyi, Bianka K
dc.contributor.authorDohrke, Jan-Niklas
dc.contributor.authorWatson, Jake F
dc.contributor.authorZhang, Danyang
dc.contributor.authorHo, Hinze
dc.contributor.authorShaikh, Saher A
dc.contributor.authorLape, Remigijus
dc.contributor.authorKrieger, James M
dc.contributor.authorGreger, Ingo H
dc.date.accessioned2022-03-14T02:03:47Z
dc.date.available2022-03-14T02:03:47Z
dc.date.issued2022-02-08
dc.identifier.issn2041-1723
dc.identifier.otherPMC8826358
dc.identifier.other35136046
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334934
dc.description.abstractAMPA-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.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101528555
dc.sourceessn: 2041-1723
dc.subjectAnimals
dc.subjectHumans
dc.subjectRats
dc.subjectGlutamic Acid
dc.subjectCalcium Channels
dc.subjectReceptors, AMPA
dc.subjectRecombinant Proteins
dc.subjectCryoelectron Microscopy
dc.subjectPatch-Clamp Techniques
dc.subjectTransfection
dc.subjectSynaptic Transmission
dc.subjectMutation
dc.subjectHEK293 Cells
dc.subjectProtein Domains
dc.titleMechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor.
dc.typeArticle
dc.date.updated2022-03-14T02:03:46Z
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume13
dc.identifier.doi10.17863/CAM.82372
dcterms.dateAccepted2022-01-13
rioxxterms.versionofrecord10.1038/s41467-022-28404-7
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidHerguedas, Beatriz [0000-0003-2044-4795]
dc.contributor.orcidWatson, Jake F [0000-0002-8698-3823]
dc.contributor.orcidHo, Hinze [0000-0003-1082-9851]
dc.contributor.orcidShaikh, Saher A [0000-0002-6162-5472]
dc.contributor.orcidKrieger, James M [0000-0001-6194-6244]
dc.contributor.orcidGreger, Ingo H [0000-0002-7291-2581]
dc.identifier.eissn2041-1723
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/N002113/1)
pubs.funder-project-idMedical Research Council (MC_U105174197)
cam.issuedOnline2022-02-08


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International