Journal
SCIENCE ADVANCES
Volume 7, Issue 46, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abj3221
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Funding
- German Research Foundation (Deutsche Forschungsgemeinschaft) [ZI 552/4-2]
- Sigrid Juselius Foundation
- Jane and Aatos Erkko Foundation
- Academy of Finland [294652, 338176]
- University of Helsinki
- Magnus Ehrnrooth Foundation
- Max Planck Society
- Academy of Finland (AKA) [294652, 294652] Funding Source: Academy of Finland (AKA)
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Mitochondrial NADH:ubiquinone oxidoreductase (complex I) is a 1-MDa membrane protein complex involved in energy metabolism. The complex drives proton translocation through redox reactions, contributing to the proton motive force for ATP synthase. Multiple structures of complex I have been determined, shedding light on its catalytic mechanism and proton pumping mechanism.
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-angstrom resolution, which reveals the positions of more than 1600 protein-bound water molecules, of which similar to 100 are located in putative proton translocation pathways. Another structure of the same complex under steady-state activity conditions at 3.4-angstrom 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 dynamic simulations, we define details of the proton translocation pathways and offer insights into the redox-coupled proton pumping mechanism of complex I.
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