Molecule of the Month: Complex I

Complex I, also known as NADH:quinone oxidoreductase, performs the first step in respiratory electron transport, the process that creates much of the energy that powers our cells. Complex I is a huge membrane-bound molecular machine that links two different reactions: the transport of electrons from NADH to ubiquinone, and the transport of protons across a membrane. In our mitochondria, this is used to create the electrochemical gradient that powers ATP synthase, powered by NADH produced by the breakdown of food molecules. Our complex I is one of the largest membrane-bound protein complexes that has been discovered, composed of 46 chains. A simpler bacterial complex I is shown here, from PDB entries 3m9s and 3rko , which is composed of 14 protein chains.

The peripheral arm of complex I (shown here in shades of red and yellow) performs the electron transport reaction. A site near the top captures NADH, the carrier molecule that transports hydrogen atoms from food molecules. Complex I then strips the electrons from these hydrogen atoms using a FMN (flavin mononucleotide) cofactor, and ships them down a chain of iron-sulfur clusters. Finally, the electrons are placed on ubiquinone molecule, which will carry the electrons to the next complex in the electron transport chain: cytochrome bc1.

The membrane-bound portion of complex I (shown here in green, blue and purple) pumps protons across a membrane. Each pair of electrons obtained from NADH will power the transport of 4 protons. Remarkably, the structure reveals that each of these protons is transported by a dedicated protein pump. Complex I has chain of transporters, all arranged in a row. The final transporter in the chain, colored green here, has a tail that reaches back and links all the transporters, and is thought to synchronize the electron transport reaction with the proton pumping cycle in all four transporters.

The transporters in complex I look very similar to simpler transporters, such as the Na+/H+ antiporter shown here (PDB entry 1zcd ). They contain a bundle of parallel alpha helices that form a pore at their center, with a charged amino acid blocking the pore at the center. In small antiporters, a negatively-charged amino acid is often used to form this gate, but in complex I, positively-charged lysines appear to play this role.