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The redox-coupled proton-channel opening in cytochrome c oxidase

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Abstract

Cytochrome c oxidase (CcO), a redox-coupled proton pump, catalyzes the reduction of molecular oxygen to water, thereby establishing the transmembrane proton gradient that fuels ATP synthesis. CcO employs two channels for proton uptake, the D- and the K-channel. In contrast to the D-channel, the K-channel does not constitute a continuous pathway of H-bonds for proton conduction and is only active in the reductive phase rendering its proton transport mechanism enigmatic. Theoretical studies have suggested selective hydration changes within the K-channel to become activated and being essential for vectorial proton transport. Here, we unravel a previously unidentified mechanism for transient proton channel activation by combining computational studies with site-directed nano-environmental probing of protonation, structural changes, and water dynamics. We show that electrostatic changes at the binuclear center lead to long-range conformational changes propagating to the K-channel entrance as evidenced by time-resolved fluorescence depolarization experiments and molecular dynamics (MD) simulations. These redox-induced long-range structural rearrangements affect the H-bond network at the K-channel's protein surface as shown by pKa-shift analysis of a local probe in experiment and simulation. Concomitantly, selective channel hydration at the K-channel entrance was revealed by dipolar relaxation studies to be associated with channel opening. We propose that instead of a singular change, it is the intricate interplay of these individual redox-triggered changes in the cause–effect relationship that defines the mechanism for transient proton conduction of the K-channel.

Graphical abstract: The redox-coupled proton-channel opening in cytochrome c oxidase

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Supplementary files

Article information


Submitted
20 Dec 2019
Accepted
27 Feb 2020
First published
27 Feb 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

The redox-coupled proton-channel opening in cytochrome c oxidase

A. Wolf, J. Dragelj, J. Wonneberg, J. Stellmacher, J. Balke, A. L. Woelke, M. Hodoscek, E. W. Knapp and U. Alexiev, Chem. Sci., 2020, Advance Article , DOI: 10.1039/C9SC06463J

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