Protein Essential for Cell Health is Avid Multitasker: TH is among least-studied mitochondrial enzymes

Researchers have found that a protein vital for cell health that has recently been associated with cancer and diabetes, can juggle its cellular to-do list—in effect having two alike protein parts split the workload. A key protein for most life forms—the TH enzyme (transhydrogenase)—works inside mitochondria. “Despite its importance, TH has been one of the least-studied mitochondrial enzymes,” says C. David Stout, PhD, scientist, The Scripps Research Institute, La Jolla, Calif, whose group led the research. “Key details we’ve been lacking include the structure of TH’s transmembrane portion, and the way in which the parts assemble into the whole enzyme,” says Josephine H. Leung, a graduate student in the Stout laboratory and the study’s lead author. The team discovered that two identical copies of TH are tied together, and one copy seems to be engaged in proton transport, the other in NADPH production. “Our new study helps clear up some mysteries – suggesting how the enzyme structure might harness protons and indicating that its two sides are able to alternate functions, always staying in balance,” Stout says. The “domain III” structure, which binds NADPH’s precursor molecule during NADPH synthesis (see image), is coupled with TH’s transmembrane structure. It had been a mystery to scientists how two such structures could function as they do without getting in each other’s way. The researchers believe the side-by-side structures are extremely flexible and positioned differently. “Our most striking finding was that the two domain III structures are not symmetric—one of them faces up while the other faces down,” Leung says. Published recently in the journal Science, the new study, titled “Division of labor in transhydrogenase by alternating proton translocation and hydride transfer,” sheds light on this process. It can be found here: bit.ly/1A8Ia1V Image: The crystal structure of TH shows two copies of the molecule (left and right), each of which contains three domains (I, II, III). Structural asymmetry is observed for domain III: One of the structures is facing up (green) to catalyze the production of NADPH from its precursor (black spheres); the other is facing down (magenta) towards the transmembrane domain II to facilitate the transit of a proton. Labels "in" and "out" denote the mitochondrial matrix and the space outside the inner mitochondrial membrane, respectively. (Image credit: C. David Stout/The Scripps Research Institute)