Abstract
Respiratory complex I plays a central role in cellular energy metabolism coupling NADH oxidation to proton translocation. In humans its dysfunction is associated with degenerative diseases. Here we report the structure of the electron input part of Aquifex aeolicus complex I at up to 1.8 Å resolution with bound substrates in the reduced and oxidized states. The redox states differ by the flip of a peptide bond close to the NADH binding site. The orientation of this peptide bond is determined by the reduction state of the nearby [Fe-S] cluster N1a. Fixation of the peptide bond by site-directed mutagenesis led to an inactivation of electron transfer and a decreased reactive oxygen species (ROS) production. We suggest the redox-gated peptide flip to represent a previously unrecognized molecular switch synchronizing NADH oxidation in response to the redox state of the complex as part of an intramolecular feed-back mechanism to prevent ROS production.
Highlights
Respiratory complex I plays a central role in cellular energy metabolism coupling NADH oxidation to proton translocation
The Lshaped complex is structured into a peripheral arm that protrudes into the aqueous milieu and catalyzes electron transfer with one FMN and 8–10 iron–sulfur ([Fe–S]) clusters, and a membrane arm embedded in the lipid bilayer that mediates proton translocation[12,13,14,15]
Crystals of A. aeolicus NuoEF contain two NuoEF heterodimers per asymmetric unit. Both monomers align with a root-mean-squared deviation (RMSD) of 0.17 Å for all atoms and will not be discussed separately
Summary
Respiratory complex I plays a central role in cellular energy metabolism coupling NADH oxidation to proton translocation. The energy-converting NADH:ubiquinone oxidoreductase, respiratory complex I, is the first enzyme complex of most respiratory chains[1,2,3,4,5,6,7] It is a major source of reactive oxygen species (ROS)[8], implicating a role in ageing[9], and its dysfunction was suggested to be related to human neurodegenerative diseases[10,11]. The Lshaped complex is structured into a peripheral arm that protrudes into the aqueous milieu and catalyzes electron transfer with one FMN and 8–10 iron–sulfur ([Fe–S]) clusters, and a membrane arm embedded in the lipid bilayer that mediates proton translocation[12,13,14,15]. When N1a is reduced, the reaction product, NAD+, cannot be ejected from its binding site and blocks the site preventing further ROS production
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