Structural Insights Into the Opening Mechanism of C1C2 Channelrhodopsin

Matthias Mulder, Songhwan Hwang, Matthias Broser, Steffen Brünle, Petr Skopintsev, Caspar Schattenberg, Christina Schnick, Sina Hartmann, Jonathan Church, Igor Schapiro, Florian Dworkowski, Tobias Weinert, Peter Hegemann, Han Sun*, Jörg Standfuss*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Channelrhodopsins, light-gated cation channels, enable precise control of neural cell depolarization or hyperpolarization with light in the field of optogenetics. This study integrates time-resolved serial crystallography and atomistic molecular dynamics (MD) simulations to resolve the structural changes during C1C2 channelrhodopsin activation. Our observations reveal that within the crystal environment, C1C2 predominantly remains in a light-activated state with characteristics of the M390 intermediate. Here, rearrangement of retinal within its binding pocket partially opens the central gate toward the extracellular vestibule. These structural changes initiate channel opening but were insufficient to allow K+ flow. Adjusting protonation states to represent the subsequent N520 intermediate in our MD simulations induced further conformational changes, including rearrangements of transmembrane helices 2 and 7, that opened the inner gate and the putative ion-translocation pathway. This allowed spontaneous cation conduction with low conductance, aligning with experimental findings. Our findings provide critical structural insights into key intermediates of the channel opening mechanism, enhancing our understanding of ion conduction and selectivity in channelrhodopsins at an atomistic level.

Original languageEnglish
JournalJournal of the American Chemical Society
DOIs
StateAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.

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