The quaternary structure of a calcium-permeable AMPA receptor: conservation of shape and symmetry across functionally distinct subunit assemblies.
AMPA receptors (AMPA-Rs) are formed as heterotetrameric combinations of subunits known as GluR1-GluR4. The calcium permeability of AMPA-Rs is controlled by the identity of the amino-acid side chain contributed by each subunit at a key position in the conductance pathway, which can be either a glutamine (Q) or an arginine (R). Tetramers assembled only from Q-containing subunits are calcium permeable. In contrast, tetramers that incorporate R-containing subunits are calcium impermeable. Both forms play key roles in physiological and pathophysiological processes in the central nervous system. Here, using electron microscopy, we present the first quaternary structure of a calcium-permeable Q-homomeric AMPA-R. The receptor is elongated, with overall 2-fold symmetry and a large central vestibule. It is thus similar to the structure previously reported for an AMPA-R assembled exclusively from R-subunits. Both structures differ from those reported for brain-derived but urea-washed "native" AMPA-Rs, which exhibited multiple asymmetrical conformations. However, even transient exposure of our Q-homomeric AMPA-Rs to urea significantly attenuates the binding of a conformationally specific antibody. As a result, we propose a model in which all AMPA-Rs share a 2-fold symmetrical structure and in which subunit-dependent differences in assembly, trafficking, and electrophysiology are mediated within the framework of fundamentally similar quaternary conformations.
Midgett
Charles R
CR
Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, NH 03755, USA.
Madden
Dean R
DR
D002118:Calcium / Q000378:metabolism; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000737:chemistry
D021122:Protein Subunits; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D014508:Urea; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium