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Structure of the Deactive State of Mammalian Respiratory Complex I

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JournalStructure
DateAccepted/In press - 27 Dec 2017
DatePublished (current) - 6 Feb 2018
Issue number2
Volume26
Pages (from-to)312-319.e3
Original languageEnglish

Abstract

Complex I (NADH:ubiquinone oxidoreductase) is central to energy metabolism in mammalian mitochondria. It couples NADH oxidation by ubiquinone to proton transport across the energy-conserving inner membrane, catalyzing respiration and driving ATP synthesis. In the absence of substrates, active complex I gradually enters a pronounced resting or deactive state. The active-deactive transition occurs during ischemia and is crucial for controlling how respiration recovers upon reperfusion. Here, we set a highly active preparation of Bos taurus complex I into the biochemically defined deactive state, and used single-particle electron cryomicroscopy to determine its structure to 4.1 Å resolution. We show that the deactive state arises when critical structural elements that form the ubiquinone-binding site become disordered, and we propose reactivation is induced when substrate binding to the NADH-reduced enzyme templates their reordering. Our structure both rationalizes biochemical data on the deactive state and offers new insights into its physiological and cellular roles. Blaza et al. used electron cryomicroscopy together with PEGylated gold grids to determine the structure of the deactive state of mammalian complex I, which is formed during ischemia, and showed it is characterized by localized unfolding around the quinone-binding site.

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© 2018 The Authors

    Research areas

  • NADH:ubiquinone oxidoreductase, PEGylated gold grid, cryo-EM, disordered protein structure, electron transport chain, membrane protein, mitochondria

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