A vital characteristic of living systems is their ability to produce biological energy (ATP) efficiently. ATP is essential for cellular functions including biosynthesis, transport, signal transduction, chemo- and photo-taxis and thermogenesis. Energy producing complexes are widespread among organisms, and their improper function leads to devastating health problems and human diseases and low crop yields in plants. The long-term goal of this project is to understand the structure, mechanism of function and biogenesis of cytochrome (cyt) components of energy pathways. Bacteria provide excellent model systems for these studies that are pertinent to eukaryotic organelles. This project will use molecular genetics, proteomics, biochemical and biophysical approaches, with a sharp focus on the critical links between the structure-function and the biogenesis of the membrane-bound cyt bc1. This is a crucial enzyme whose absence or malfunction is the cause of multiple human diseases, including many muscular and neurological disorders. Resolution of the 3D structure of the cyt bc1 revealed the mobility of its FeS protein subunit, and is now leading to a chemical description of its mechanism of function, while our understanding of its biogenesis remains rudimentary even in simpler bacteria.
The specific aims i nclude probing the control mechanisms of the FeS protein motion to avoid unwanted side reactions, creating novel bc1 complex variants to visualize the internal reaction steps that are difficult to monitor, and characterizing novel biogenesis components of energy transducing cyt c complexes, including incorporation of their prosthetic groups. These studies will greatly enhance our understanding and knowledge of the structure, mechanism of function and biogenesis of the cyt bc1 as a prototype enzyme. Insights gained using this simpler system are generally applicable to the structurally more complex and yet functionally similar organelle-derived complexes, and could provide guiding lights for elucidating the molecular bases of mitochondrial and other human diseases and aging.
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