Structure of mammalian respiratory complex I.

TitleStructure of mammalian respiratory complex I.
Publication TypeJournal Article
Year of Publication2016
AuthorsZhu, J, Vinothkumar, KR, Hirst, J
JournalNature
Volume536
Issue7616
Pagination354-8
Date Published2016 08 18
ISSN1476-4687
KeywordsAnimals, Binding Sites, Biocatalysis, Cattle, Cell Hypoxia, Cryoelectron Microscopy, Electron Transport Complex I, Mitochondria, Heart, Models, Molecular, Movement, Oxidation-Reduction, Protein Structure, Tertiary, Protein Subunits, Protons, Ubiquinone
Abstract

Complex I (NADH:ubiquinone oxidoreductase), one of the largest membrane-bound enzymes in the cell, powers ATP synthesis in mammalian mitochondria by using the reducing potential of NADH to drive protons across the inner mitochondrial membrane. Mammalian complex I (ref. 1) contains 45 subunits, comprising 14 core subunits that house the catalytic machinery (and are conserved from bacteria to humans) and a mammalian-specific cohort of 31 supernumerary subunits. Knowledge of the structures and functions of the supernumerary subunits is fragmentary. Here we describe a 4.2-Å resolution single-particle electron cryomicroscopy structure of complex I from Bos taurus. We have located and modelled all 45 subunits, including the 31 supernumerary subunits, to provide the entire structure of the mammalian complex. Computational sorting of the particles identified different structural classes, related by subtle domain movements, which reveal conformationally dynamic regions and match biochemical descriptions of the 'active-to-de-active' enzyme transition that occurs during hypoxia. Our structures therefore provide a foundation for understanding complex I assembly and the effects of mutations that cause clinically relevant complex I dysfunctions, give insights into the structural and functional roles of the supernumerary subunits and reveal new information on the mechanism and regulation of catalysis.

DOI10.1038/nature19095
Alternate JournalNature
Citation Key10.1038/nature19095
PubMed ID27509854
PubMed Central IDPMC5027920
Grant ListMC_U105663141 / / Medical Research Council / United Kingdom
U105184322 / / Medical Research Council / United Kingdom
U105663141 / / Medical Research Council / United Kingdom