title: Elucidation of AMPA receptor-stargazin complexes by cryo-electron microscopy.
abstract: AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and contribute to high cognitive processes such as learning and memory. In the brain, AMPAR trafficking, gating, and pharmacology is tightly controlled by transmembrane AMPAR regulatory proteins (TARPs). Here, we used cryo-electron microscopy to elucidate the structural basis of AMPAR regulation by one of these auxiliary proteins, TARP γ2, or stargazin (STZ). Our structures illuminate the variable interaction stoichiometry of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR. Analysis of the AMPAR-STZ binding interfaces suggests that electrostatic interactions between the extracellular domains of AMPAR and STZ play an important role in modulating AMPAR function through contact surfaces that are conserved across AMPARs and TARPs. We propose a model explaining how TARPs stabilize the activated state of AMPARs and how the interactions between AMPARs and their auxiliary proteins control fast excitatory synaptic transmission.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA. Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Twomey
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Yelshanskaya
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA. Howard Hughes Medical Institute, 650 West 168th Street, New York, NY 10032, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Grassucci
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA. Department of Biological Sciences, Columbia University, 650 West 168th Street, New York, NY 10032, USA. Howard Hughes Medical Institute, 650 West 168th Street, New York, NY 10032, USA. as4005@cumc.columbia.edu jf2192@cumc.columbia.edu.
authors.forename: Joachim
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA. as4005@cumc.columbia.edu jf2192@cumc.columbia.edu.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Sobolevsky
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry* / Q000648:ultrastructure; D020285:Cryoelectron Microscopy; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D055550:Protein Stability; D017433:Protein Structure, Secondary; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry* / Q000648:ultrastructure; D009435:Synaptic Transmission
chemical_list: C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2