Structures of channelrhodopsin paralogs in peptidiscs explain their contrasting K+ and Na+ selectivities

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Abstract

Kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) is a light-gated channel used for optogenetic silencing of mammalian neurons. It selects K+ over Na+ in the absence of the canonical tetrameric K+ selectivity filter found universally in voltage- and ligand-gated channels. The genome of H. catenoides also encodes a highly homologous cation channelrhodopsin (HcCCR), a Na+ channel with >100-fold larger Na+ to K+ permeability ratio. Here, we use cryo-electron microscopy to determine atomic structures of these two channels embedded in peptidiscs to elucidate structural foundations of their dramatically different cation selectivity. Together with structure-guided mutagenesis, we show that K+ versus Na+ selectivity is determined at two distinct sites on the putative ion conduction pathway: in a patch of critical residues in the intracellular segment (Leu69/Phe69, Ile73/Ser73 and Asp116) and within a cluster of aromatic residues in the extracellular segment (primarily, Trp102 and Tyr222). The two filters are on the opposite sides of the photoactive site involved in channel gating.

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Morizumi, T., Kim, K., Li, H., Govorunova, E. G., Sineshchekov, O. A., Wang, Y., … Ernst, O. P. (2023). Structures of channelrhodopsin paralogs in peptidiscs explain their contrasting K+ and Na+ selectivities. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-40041-2

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