Architecture and structural dynamics of the heteromeric GluK2/K5 kainate receptor
- Weill Cornell Medical College, United States
- McGill University, Canada
Abstract
Kainate receptors (KARs) are L-glutamate-gated ion channels that regulate synaptic transmission and modulate neuronal circuits. KARs have strict assembly rules and primarily function as heteromeric receptors in the brain. A longstanding question is how KAR heteromer subunits organize and coordinate together to fulfill their signature physiological roles. Here we report structures of the GluK2/GluK5 heteromer in apo, antagonist-bound, and desensitized states. The receptor assembles with two copies of each subunit, ligand binding domains arranged as two heterodimers, and GluK5 subunits proximal to the channel. Strikingly, during desensitization GluK2 but not GluK5 subunits undergo major structural rearrangements to facilitate channel closure. We show how the large conformational differences between antagonist-bound and desensitized states are mediated by the linkers connecting the pore helices to the ligand-binding domains. This work presents the first KAR heteromer structure, reveals how its subunits are organized, and resolves how the heteromer can accommodate functionally-distinct closed channel structures.
Data availability
Cryo-EM density maps have been deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-23017 (GluK2/K5-apo), EMD-23014 (GluK2/K5-CNQX), and EMD-23015 (GluK2/K5-L-Glu). Model coordinates have been deposited in the Protein Data Bank (PDB) under accession numbers 7KS0 (GluK2/K5-CNQX) and 7KS3 (GluK2/K5-L-Glu). Raw cryo-EM data will be publicly available on the EMPIAR repository upon publication under the accession numbers: EMPIAR-10658, EMPIAR-10659, EMPIAR-10660
Article and author information
Author details
Patricia MGE Brown
Funding
Leon Levy Foundation (N/A)
- Joel Meyerson
Fonds de Recherche du Québec - Santé (N/A)
- Patricia MGE Brown
Canadian Institutes of Health Research (136832)
- Derek Bowie
Canadian Institutes of Health Research (162317)
- Derek Bowie
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Merritt Maduke, Stanford University School of Medicine, United States
Publication history
- Received: December 29, 2020
- Accepted: March 5, 2021
- Accepted Manuscript published: March 16, 2021 (version 1)
- Version of Record published: March 26, 2021 (version 2)
- Version of Record updated: April 9, 2021 (version 3)
- Version of Record updated: April 20, 2021 (version 4)
Copyright
© 2021, Khanra et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Architecture and structural dynamics of the heteromeric GluK2/K5 kainate receptor
eLife 10:e66097.
https://doi.org/10.7554/eLife.66097
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