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Structure. 2018 Feb 6;26(2):312-319.e3. doi: 10.1016/j.str.2017.12.014. Epub 2018 Jan 26.

Structure of the Deactive State of Mammalian Respiratory Complex I.

Author information

1
MRC Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
2
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
3
MRC Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. Electronic address: jh@mrc-mbu.cam.ac.uk.

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.

KEYWORDS:

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

PMID:
29395787
PMCID:
PMC5807054
DOI:
10.1016/j.str.2017.12.014
[Indexed for MEDLINE]
Free PMC Article

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