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Stanford University

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Cell, Available online 30 August 2023 | https://doi.org/10.1016/j.cell.2023.08.009 Structural basis for ion selectivity in potassium-selective channelrhodopsins

Seiya Tajima^1,15, Yoon Seok Kim ^2,15, Masahiro Fukuda¹, YoungJu Jo ², Peter Y. Wang ², Joseph M. Paggi ³, Masatoshi Inoue ², Eamon F.X. Byrne ², Koichiro E. Kishi ¹, Seiwa Nakamura ¹, Charu Ramakrishnan ⁴, Shunki Takaramoto ⁵, Takashi Nagata ⁵, Masae Konno ^5,6, Masahiro Sugiura ⁷, Kota Katayama ⁷, Toshiki E. Matsui ¹, Keitaro Yamashita ⁸, Suhyang Kim ¹, Hisako Ikeda¹, Jaeah Kim ², Hideki Kandori ^7,9, Ron O. Dror ^3,10, Keiichi Inoue ⁵, Karl Deisseroth^2,4,11,12,16, Hideaki E. Kato ^1,13,14

¹Komaba Institute for Science, The University of Tokyo, Meguro, Tokyo, Japan
²Department of Bioengineering, Stanford University, Stanford, CA, USA
³Department of Computer Science, Stanford University, Stanford, CA, USA
⁴CNC Program, Stanford University, Stanford, CA, USA
⁵The Institute for Solid State Physics, The University of Tokyo, Kashiwa, Japan
⁶PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan
⁷Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Showa-ku, Japan
⁸MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK
⁹OptoBioTechnology Research Center, Nagoya Institute of Technology, Showa-ku, Japan
¹⁰Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA
¹¹Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
¹²Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
¹³Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan
¹⁴FOREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan
¹⁵These authors contributed equally
¹⁶Lead contact

Corresponding authors: Karl Deisseroth, Hideaki E. Kato

Abstract

KCR channelrhodopsins (K⁺-selective light-gated ion channels) have received attention as potential inhibitory optogenetic tools but more broadly pose a fundamental mystery regarding how their K⁺ selectivity is achieved. Here, we present 2.5–2.7 Å cryo-electron microscopy structures of HcKCR1 and HcKCR2 and of a structure-guided mutant with enhanced K⁺ selectivity. Structural, electrophysiological, computational, spectroscopic, and biochemical analyses reveal a distinctive mechanism for K⁺ selectivity; rather than forming the symmetrical filter of canonical K⁺ channels achieving both selectivity and dehydration, instead, three extracellular-vestibule residues within each monomer form a flexible asymmetric selectivity gate, while a distinct dehydration pathway extends intracellularly. Structural comparisons reveal a retinal-binding pocket that induces retinal rotation (accounting for HcKCR1/HcKCR2 spectral differences), and design of corresponding KCR variants with increased K⁺ selectivity (KALI-1/KALI-2) provides key advantages for optogenetic inhibition in vitro and in vivo. Thus, discovery of a mechanism for ion-channel K⁺ selectivity also provides a framework for next-generation optogenetics.

논문정보

형식Research article
게재일2023년 08월 (BRIC 등록일 2023-08-31)
연구진국외 연구진
분야 생명과학 > 생화학

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