The mitochondrial F1Fo ATP synthase is responsible for the synthesis 90% of the ATP under aerobic conditions. The mitochondrial ATP synthase is a multimeric protein complex with an overall molecular weight greater than 550,000 Da. A portion of the ATP synthase is embedded in the mitochondrial membrane and acts as a proton turbine and a portion is in the matrix space and acts as a rotary engine that phosphorylates ADP. Despite many people*decades devoted across the globe, the structure of the entire enzyme complex has remained elusive. Because of recent technological advances and progress, we are now on the brink of obtaining the high-resolution structure of the mitochondrial enzyme. One key unanswered question is: what are the molecular determinants that cause the central stalk to rotate during ATP synthesis and hydrolysis? A principal goal of this project is to determine the high-resolution crystal structure of the eukaryotic ATP synthase complex.
This aim will give critical structural details into the understanding of the mechanism of proton translocation coupled to rotation driving ATP synthesis or driven by ATP hydrolysis. We will investigate the structural relationship of the ATP synthase in a number of reaction intermediate structures with inhibitors bound. We will exploit our understanding of the structure and biochemistry of the ATP synthase and aim to gain a further understanding of human mitochondrial diseases and variations amongst the population. This study will help bridge the knowledge gap between the genomic studies and biochemistry and will allow for translation into healthcare. Overall, the project will provide basic understanding on the mechanism of proton translocation coupled to an energy-requiring event - the synthesis of ATP from ADP and Pi - and aid in knowledge-based decisions in both the health and disease.
This study will advance our understanding of the mechanism of ATP synthase and coupling of ion translocation to the synthesis of ATP. Coupled with biochemical studies on the effect of disease causing mutations that affect the enzyme function, the results herein will lead to advances to the treatment of diseases and adverse health conditions.
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| Xu, Ting; Pagadala, Vijayakanth; Mueller, David M (2015) Understanding structure, function, and mutations in the mitochondrial ATP synthase. Microb Cell 2:105-125 |
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| Symersky, Jindrich; Osowski, Daniel; Walters, D Eric et al. (2012) Oligomycin frames a common drug-binding site in the ATP synthase. Proc Natl Acad Sci U S A 109:13961-5 |
| Symersky, Jindrich; Pagadala, Vijayakanth; Osowski, Daniel et al. (2012) Structure of the c(10) ring of the yeast mitochondrial ATP synthase in the open conformation. Nat Struct Mol Biol 19:485-91, S1 |
| Pagadala, Vijayakanth; Vistain, Luke; Symersky, Jindrich et al. (2011) Characterization of the mitochondrial ATP synthase from yeast Saccharomyces cerevisae. J Bioenerg Biomembr 43:333-47 |
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