Structural dynamics of the GluK3-kainate receptor neurotransmitter binding domains revealed by cryo-EM

Jyoti Kumari, Ameya D. Bendre, Sumedha Bhosale, Rajesh Vinnakota, Ananth P. Burada, Giancarlo Tria, Raimond B. G. Ravelli, Peter J. Peters, Manali Joshi, Janesh Kumar*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Kainate receptors belong to the ionotropic glutamate receptor family and play critical roles in the regulation of synaptic networks. The kainate receptor subunit GluK3 has unique functional properties and contributes to presynaptic facilitation at the hippocampal mossy fiber synapses along with roles at the post-synapses. To gain structural insights into the unique functional properties and dynamics of GluK3 receptor, we imaged them via electron microscopy in the apo-state and in complex with either agonist kainate or antagonist UBP301. Our analysis of all the GIuK3 full-length structures not only provides insights into the receptor transitions between desensitized and closed states but also reveals a "non-classical" conformation of neurotransmitter binding domain in the closed-state distinct from that observed in AMPA and other kainate receptor structures. We show by molecular dynamics simulations that Asp759 influences the stability of the LBD dimers and hence could be responsible for the observed conformational variability and dynamics of the GIuK3 via electron microscopy. Lower dimer stability could explain faster desensitization and low agonist sensitivity of GluK3. In overview, our work helps to associate biochemistry and physiology of GluK3 receptors with their structural biology and offers structural insights into the unique functional properties of these atypical receptors. (C) 2020 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)1051-1058
Number of pages8
JournalInternational Journal of Biological Macromolecules
Volume149
DOIs
Publication statusPublished - 15 Apr 2020

Keywords

  • Glutamate receptor
  • Cryo-electron microscopy
  • Kainate
  • GLUTAMATE-RECEPTOR
  • GLUK3
  • AMPA
  • IMPLEMENTATION
  • GLUR7

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