Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor

DOI: 10.1038/s41467-022-28404-7

Authors: Beatriz Herguedas (MRC Laboratory of Molecular Biology; University of Zaragoza) , Bianka K. Kohegyi (MRC Laboratory of Molecular Biology) , Jan-Niklas Dohrke (MRC Laboratory of Molecular Biology; Universitätsmedizin Göttingen, Georg-August-Universität) , Jake F. Watson (MRC Laboratory of Molecular Biology; Institute of Science and Technology (IST) Austria) , Danyang Zhang (MRC Laboratory of Molecular Biology) , Hinze Ho (MRC Laboratory of Molecular Biology; University of Cambridge) , Saher A. Shaikh (MRC Laboratory of Molecular Biology) , Remigijus Lape (MRC Laboratory of Molecular Biology) , James M. Krieger (MRC Laboratory of Molecular Biology) , Ingo H. Greger (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 13

State: Published (Approved)
Published: February 2022
Diamond Proposal Number(s): 23268

Abstract: AMPA-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.

Journal Keywords: Cryoelectron microscopy; Ion channels in the nervous system'Ligand-gated ion channels; Permeation and transport

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios III-Titan Krios III at Diamond

Added On: 14/02/2022 10:41

Documents:
s41467-022-28404-7.pdf

Discipline Tags:

Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)