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- W2790228664 abstract "A variety of de novo missense mutations associated with neurological disorders occur in ionotropic glutamate receptors (iGluRs) subunits. These disease mutations often appear in motifs critical to the process of glutamate-induced channel opening or gating. Numerous missense mutations are found in the NMDA receptor M4 segments, a transmembrane segment peripheral to the pore domain in eukaryotic iGluRs. Subsets of these missense mutations affect receptor gating but very dramatic effects, including in one instance halting gating, occurred at a conserved glycine, positioned at the extracellular end of M4. Even alanine substitutions at this glycine, most notably in GluN1, severely restricted the stability of the open state. Molecular dynamics simulations suggest that this glycine in GluN1 permits unique backbone interactions as well as the extreme extracellular end of M4 to unravel in the open state. Surprisingly, in an AMPAR structure, reorientation of the extreme extracellular end of M4 centered on this conserved glycine occurs, but in contrast to NMDARs, in a closed state. Consistent with these structural differences, an alanine substitution at this glycine in AMPARs destabilizes a closed state, in direct contrast to that for NMDARs. Hence, structural features unique to glycine stabilize opposing conformations in iGluR subtypes. In NMDARs, missense mutations at this conserved glycine dramatically alter their function at synapses. These results have strong implications for how such disorders are caused at the ion channel level and highlight how structural features in NMDAR and AMPAR have evolved to permit them to carry out different functional roles at synapses." @default.
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- W2790228664 date "2018-02-01" @default.
- W2790228664 modified "2023-09-27" @default.
- W2790228664 title "Disease-Associated Mutations Reveal a Conserved Glycine that Stabilizes Opposing Channel Conformations in Ionotropic Glutamate Receptors" @default.
- W2790228664 doi "https://doi.org/10.1016/j.bpj.2017.11.1752" @default.
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