High-resolution structure and dynamics of mitochondrial complex I - insights into the proton pumping mechanism

Parey, K.; Lasham, J.; Mills, D. J.; Djurabekova, A.; Haapanen, O.; Galemou Yoga, E.; Xie, H.; Kühlbrandt, W.; Sharma, V.; Vonck, J.; Zickermann, V.

doi:10.1101/2021.04.16.440187

bioRxiv · 10.1101/2021.04.16.440187

High-resolution structure and dynamics of mitochondrial complex I - insights into the proton pumping mechanism

Parey, K.·Lasham, J.·Mills, D. J.·Djurabekova, A.·Haapanen, O.·Galemou Yoga, E.·Xie, H.·Kühlbrandt, W.·Sharma, V.·Vonck, J.·Zickermann, V.

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Abstract

Mitochondrial NADH:ubiquinone oxidoreductase (complex I) is a 1 MDa membrane protein complex with a central role in energy metabolism. Redox-driven proton translocation by complex I contributes substantially to the proton motive force that drives ATP synthase. Several structures of complex I from bacteria and mitochondria have been determined but its catalytic mechanism has remained controversial. We here present the cryo-EM structure of complex I from Yarrowia lipolytica at 2.1 [A] resolution, which reveals the positions of more than 1600 protein-bound water molecules, of which [~]100 are located in putative proton translocation pathways. Another structure of the same complex under steady-state activity conditions at 3.4 [A] resolution indicates conformational transitions that we associate with proton injection into the central hydrophilic axis. By combining high-resolution structural data with site-directed mutagenesis and large-scale molecular dynamics simulations, we define details of the proton translocation pathways, and offer new insights into the redox-coupled proton pumping mechanism of complex I.

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Parey, K., Lasham, J., Mills, D. J., Djurabekova, A., Haapanen, O., Galemou Yoga, E., Xie, H., Kühlbrandt, W., Sharma, V., Vonck, J., Zickermann, V.. 2021-04-16. High-resolution structure and dynamics of mitochondrial complex I - insights into the proton pumping mechanism. https://doi.org/10.1101/2021.04.16.440187

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