title: Structure and organization of heteromeric AMPA-type glutamate receptors.
abstract: AMPA-type glutamate receptors (AMPARs), which are central mediators of rapid neurotransmission and synaptic plasticity, predominantly exist as heteromers of the subunits GluA1 to GluA4. Here we report the first AMPAR heteromer structures, which deviate substantially from existing GluA2 homomer structures. Crystal structures of the GluA2/3 and GluA2/4 N-terminal domains reveal a novel compact conformation with an alternating arrangement of the four subunits around a central axis. This organization is confirmed by cysteine cross-linking in full-length receptors, and it permitted us to determine the structure of an intact GluA2/3 receptor by cryogenic electron microscopy. Two models in the ligand-free state, at resolutions of 8.25 and 10.3 angstroms, exhibit substantial vertical compression and close associations between domain layers, reminiscent of N-methyl-D-aspartate receptors. Model 1 resembles a resting state and model 2 a desensitized state, thus providing snapshots of gating transitions in the nominal absence of ligand. Our data reveal organizational features of heteromeric AMPARs and provide a framework to decipher AMPAR architecture and signaling.
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Herguedas
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Nafría
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Cais
authors.affiliation: Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fernández-Leiro
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Krieger
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Hinze
authors.initials: H
authors.lastname: Ho
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Greger
mesh_terms: D001921:Brain / Q000378:metabolism; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D018091:Receptors, AMPA / Q000737:chemistry* / Q000648:ultrastructure
chemical_list: D008024:Ligands; D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3; C104724:glutamate receptor ionotropic, AMPA 4; C104722:glutamate receptor ionotropic, AMPA 2