Structural Arrangement Produced by Concanavalin A Binding to Homomeric GluK2 Receptors

Abstract

Kainate receptors are members of the ionotropic glutamate receptor family. They form cation-specific transmembrane channels upon binding glutamate that desensitize in the continued presence of agonists. Concanavalin A (Con-A), a lectin, stabilizes the active open-channel state of the kainate receptor and reduces the extent of desensitization. In this study, we used single-molecule fluorescence resonance energy transfer (smFRET) to investigate the conformational changes underlying kainate receptor modulation by Con-A. These studies showed that Con-A binding to GluK2 homomeric kainate receptors resulted in closer proximity of the subunits at the dimer–dimer interface at the amino-terminal domain as well as between the subunits at the dimer interface at the agonist-binding domain. Additionally, the modulation of receptor functions by monovalent ions, which bind to the dimer interface at the agonist-binding domain, was not observed in the presence of Con-A. Based on these results, we conclude that Con-A modulation of kainate receptor function is mediated by a shift in the conformation of the kainate receptor toward a tightly packed extracellular domain.

Kainate receptor channel opening and gating mechanism

“…Fast application of agonist glutamate (Glu) in the presence of the PAMs lectin concanavalin A (ConA) and BPAM344 (hereafter BPAM) enabled us to trap an ensemble of GluK2 KAR conformations, including the fully-liganded open state and Glu-bound non-conducting states. These structures reveal the unique gating mechanism of KARs, uncover the mechanism of their regulation by ConA 40 – 42 , provide molecular templates for understanding their distinct roles in the central nervous system, and suggest potential strategies for drug development to treat numerous neurological and psychiatric diseases.…”

“…the unique gating mechanism of KARs, uncover the mechanism of their regulation by ConA [40][41][42] , provide molecular templates for understanding their distinct roles in the central nervous system, and suggest potential strategies for drug development to treat numerous neurological and psychiatric diseases.…”

Advanced Research on Structure–Function Relationships of Membrane Proteins

“…Since solution NMR allows for the detecting and quantifying of proton dynamics at various timescales and at a semi-atomic resolution, the method is suitable for understanding the functions of the multi-spanning helical membrane proteins. The article by Cuauhtemoc U. Gonzalez et al [9] explores the research on the structural arrangement produced by concanavalin A (Con-A) binding to homomeric GluK2 receptors. Con-A stabilizes the active open-channel state of the kainate receptor and reduces the extent of desensitization.…”

“…The article by Cuauhtemoc U. Gonzalez et al [ 9 ] explores the research on the structural arrangement produced by concanavalin A (Con-A) binding to homomeric GluK2 receptors. Con-A stabilizes the active open-channel state of the kainate receptor and reduces the extent of desensitization.…”