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On June 14, 2019, the team of Yang Maojun, adjunct professor of College of Pharmacy of our school and College of Life Science, Tsinghua University, published research article calledCryo-EM structure of the mammalian ATP synthase tetramer bound with inhibitory protein IF1inScience. The College of Pharmacy is a joint completion unit. In the paper, the constitution form and high-resolution structure of mammalian ATP synthase tetramer have been under groundbreaking discovery and analysis. The complete structure of ATP synthase of higher organisms has been first obtained and intracellular molecular mechanism for regulation and controlling on ATP synthase has been put forward, providing an important structural basis for further understanding the subunit composition and regulatory mechanism of mammalian ATP synthase and its impact on mitochondrial morphology. At the same time, it also provides important material for the update of textbooks in the future.

Professor Yang Maojun has been deeply engaged in the study of mitochondrial respiratory chain since he set up his research team at Tsinghua University in 2008, and has made a series of important achievements, for example, the structure of mitochondrial respiratory chain super-complex has been elucidated at the atomic level for the first time; later he discovered the existence of the mitochondrial respiratory chainsuper-complex; he also analyzed the structure of the largest and most complex mammaliansuper-membraninmolecular machines analyzed in the world, besides, he explained its mechanism of action in part.

In the progress of above project, the team of Yang Maojun consistently found the presence of extremely rare particles with H-shaped molecular structures, through further analysis, showing that those particles are a type of complex of ATP synthase tetramer which is corresponding to the band of high molecular weight in CN-PAGE. Later, he designed a set of new and complete purification routes to obtain a large number of protein samples with high purity and homogeneity, and prepared a lot of frozen electron-microscope samples. After inspection, some samples were found to be of good quality and suitable for data collection.

Based on the structure, team of Yang Maojun found that ATP synthase tetramers are likely to be inhibited by at least three mechanisms. Firstly, on one side of mitochondrial matrix, IF1 shall insert its N-end deeply into the middle of a round head with catalytic activity of ATP synthase, attached to a rod that connects the transmembrane region to the head while its C-end shall form a long spiral. The most interesting thing is that this spiral shall be of various states of aggregation under the regulation of proton concentration. When the proton concentration goes up, it forms dimers, and then holds the two heads close to one side of the ATP synthase tetramer, inhibiting the movement of active center of ATP synthase so that it cannot synthetize ATP molecule. As the proton concentration decreases, IF1 protein shall form tetramers or hyperpolymers so that it pulls the N-end out of the ATP synthase head to release the inhibition. At this time, ATP synthase becomes active, synthesizing ATP.

In conclusion, the research achievement not only discovers, identifies and analyzes the complete structure of the most important protein super-complex in mitochondria for the first time, but also corrects the wrong understanding in previous scientific discoveries, and provides a new perspective for people to deeply understand how mitochondria synthesize ATP, the energy molecule necessary for our life. Meanwhile, it also has laid a good foundation for us to deeply understand the prevention and treatment of diseases related to mitochondrial respiratory chain. This research has brought a significant and far-reaching impact on the health of humans.