Structure and desensitization of AMPA receptor complexes with type II TARP γ5 and GSG1L
0303 health sciences
Patch-Clamp Techniques
Polymers
Protein Conformation
Amino Acid Motifs
Cryoelectron Microscopy
Lipid Bilayers
Molecular Conformation
Membrane Proteins
Synaptic Transmission
Rats
03 medical and health sciences
HEK293 Cells
Protein Domains
Claudins
Image Processing, Computer-Assisted
Animals
Humans
Calcium Channels
Receptors, AMPA
Dimerization
Protein Binding
DOI:
10.1016/j.molcel.2021.09.030
Publication Date:
2021-10-22T03:55:16Z
AUTHORS (5)
ABSTRACT
AMPA receptors (AMPARs) mediate the majority of excitatory neurotransmission. Their surface expression, trafficking, gating, and pharmacology are regulated by auxiliary subunits. Of the two types of TARP auxiliary subunits, type I TARPs assume activating roles, while type II TARPs serve suppressive functions. We present cryo-EM structures of GluA2 AMPAR in complex with type II TARP γ5, which reduces steady-state currents, increases single-channel conductance, and slows recovery from desensitization. Regulation of AMPAR function depends on its ligand-binding domain (LBD) interaction with the γ5 head domain. GluA2-γ5 complex shows maximum stoichiometry of two TARPs per AMPAR tetramer, being different from type I TARPs but reminiscent of the auxiliary subunit GSG1L. Desensitization of both GluA2-GSG1L and GluA2-γ5 complexes is accompanied by rupture of LBD dimer interface, while GluA2-γ5 but not GluA2-GSG1L LBD dimers remain two-fold symmetric. Different structural architectures and desensitization mechanisms of complexes with auxiliary subunits endow AMPARs with broad functional capabilities.
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