title: Crosslinking the ligand-binding domain dimer interface locks kainate receptors out of the main open state.
abstract: Kainate-selective ionotropic glutamate receptors (iGluRs) fulfil key roles in the CNS, making them the subject of detailed structural and functional analyses. Although they are known to gate a channel pore with high and low ion-permeation rates, it is still not clear how switches between these gating modes are achieved at the structural level. Here, we uncover an unexpected role for the ligand-binding domain (LBD) dimer assembly in this process. Covalent crosslinking of the dimer interface keeps kainate receptors out of the main open state but permits access to lower conductance states suggesting that significant rearrangements of the dimer interface are required for the receptor to achieve full activation. These observations differ from NMDA-selective iGluRs where constraining dimer movement reduces open-channel probability. In contrast, our data show that restricting movement of the dimer interface interferes with conformational changes that underlie both activation and desensitization. Working within the limits of a common architectural design, we propose functionally diverse iGluR families were able to emerge during evolution by re-deploying existing gating structures to fulfil different tasks.
authors.affiliation: Department of Pharmacology and Therapeutics, Bellini Building, Room 164, McGill University, 3649 Promenade Sir William Osler, Montreal, Québec, Canada.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Daniels
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Andrews
authors.forename: Mark R P
authors.initials: MR
authors.lastname: Aurousseau
authors.forename: Michael V
authors.initials: MV
authors.lastname: Accardi
authors.forename: Derek
authors.initials: D
authors.lastname: Bowie
mesh_terms: D002460:Cell Line; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000502:physiology*; D000097806:GluK2 Kainate Receptor
chemical_list: D018698:Glutamic Acid; D008024:Ligands; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor