Entire Respiratory Complex I from Thermus Thermophilus

Abstract

Abstract Complex I ( NADH :ubiquinone oxidoreductase) plays a central role in cellular energy production, coupling electron transfer between NADH and quinone to proton translocation. It is the largest protein assembly of bacterial and mitochondrial respiratory chains, and bacterial enzyme provides its important ‘minimal’ model. Dysfunction of mitochondrial complex I is implicated in many human neurodegenerative diseases. It is also a major source of reactive oxygen species ( ROS ), which may be one of the causes of Parkinson's disease and aging. The L‐shaped complex consists of a hydrophilic arm, where electron transfer occurs, and a membrane arm, where proton translocation takes place. Previously, we had solved the crystal structures of the hydrophilic domain of complex I from Thermus thermophilus and of the membrane domain from Escherichia coli . Recently, we determined the atomic structure of the intact entire complex I from T. thermophilus (536 kDa, 16 subunits, 9 iron–sulfur (Fe‐S) clusters, 64 transmembrane helices). The 95 Å long electron transfer pathway through the enzyme proceeds from the primary electron acceptor flavin mononucleotide, through seven conserved Fe‐S clusters, to the unusually elongated quinone‐binding site at the interface with the membrane domain. Four putative proton translocation channels are found in the membrane domain, all linked by the central flexible axis containing charged residues. The redox energy of electron transfer is coupled to proton translocation by the mechanism proposed to involve long‐range conformational changes.