A long road towards the structure of respiratory complex I, a giant molecular proton pump Journal Article

Author(s): Sazanov, Leonid A; Baradaran, Rozbeh ; Efremov, Rouslan G; Berrisford, John M; Minhas, Gurdeep S
Article Title: A long road towards the structure of respiratory complex I, a giant molecular proton pump
Abstract: Complex I (NADH:ubiquinone oxidoreductase) is central to cellular energy production, being the first and largest enzyme of the respiratory chain in mitochondria. It couples electron transfer from NADH to ubiquinone with proton translocation across the inner mitochondrial membrane and is involved in a wide range of human neurodegenerative disorders. Mammalian complex I is composed of 44 different subunits, whereas the 'minimal' bacterial version contains 14 highly conserved 'core' subunits. The L-shaped assembly consists of hydrophilic and membrane domains. We have determined all known atomic structures of complex I, starting from the hydrophilic domain of Thermus thermophilus enzyme (eight subunits, nine Fe-S clusters), followed by the membrane domains of the Escherichia coli (six subunits, 55 transmembrane helices) and T. thermophilus (seven subunits, 64 transmembrane helices) enzymes, and finally culminating in a recent crystal structure of the entire intact complex I from T. thermophilus (536 kDa, 16 subunits, nine Fe-S clusters, 64 transmembrane helices). The structure suggests an unusual and unique coupling mechanism via longrange conformational changes. Determination of the structure of the entire complex was possible only through this step-by-step approach, building on from smaller subcomplexes towards the entire assembly. Large membrane proteins are notoriously difficult to crystallize, and so various non-standard and sometimes counterintuitive approaches were employed in order to achieve crystal diffraction to high resolution and solve the structures. These steps, as well as the implications from the final structure, are discussed in the present review.
Keywords: Bioenergetics; Complex I; Membrane protein structure; NADH:ubiquinone oxidoreductase; Respiratory chain; X-ray crystallography
Journal Title: Biochemical Society Transactions
Volume: 41
Issue 5
ISSN: 03005127
Publisher: Portland Press  
Date Published: 2013-10-01
Start Page: 1265
End Page: 1271
Sponsor: This work was funded by the Medical Research Council.
DOI: 10.1042/BST20130193
Open access: no