Locking loop movement in the ubiquinone pocket of complex I disengages the proton pumps

Alfredo Cabrera-Orefice, Etienne Galemou Yoga, Christophe Wirth, Karin Siegmund, Klaus Zwicker, Sergio Guerrero-Castillo, Volker Zickermann, Carola Hunte and Ulrich Brandt ()
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Alfredo Cabrera-Orefice: Radboud University Medical Center
Etienne Galemou Yoga: Goethe University
Christophe Wirth: University of Freiburg
Karin Siegmund: Goethe University
Klaus Zwicker: Goethe University
Sergio Guerrero-Castillo: Radboud University Medical Center
Volker Zickermann: Goethe-University
Carola Hunte: University of Freiburg
Ulrich Brandt: Radboud University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Complex I (proton-pumping NADH:ubiquinone oxidoreductase) is the largest enzyme of the mitochondrial respiratory chain and a significant source of reactive oxygen species (ROS). We hypothesized that during energy conversion by complex I, electron transfer onto ubiquinone triggers the concerted rearrangement of three protein loops of subunits ND1, ND3, and 49-kDa thereby generating the power-stoke driving proton pumping. Here we show that fixing loop TMH1-2ND3 to the nearby subunit PSST via a disulfide bridge introduced by site-directed mutagenesis reversibly disengages proton pumping without impairing ubiquinone reduction, inhibitor binding or the Active/Deactive transition. The X-ray structure of mutant complex I indicates that the disulfide bridge immobilizes but does not displace the tip of loop TMH1-2ND3. We conclude that movement of loop TMH1-2ND3 located at the ubiquinone-binding pocket is required to drive proton pumping corroborating one of the central predictions of our model for the mechanism of energy conversion by complex I proposed earlier.

Date: 2018
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DOI: 10.1038/s41467-018-06955-y

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