Mechanisms of Nickel-Responsive Proteins

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My research program will examine the chemical properties and metal-responsive activities of proteins responsible for nickel homeostasis. Nickel is an essential nutrient for many forms of life, but it can also be toxic. Thus, organisms that use nickel have to tightly and specifically control the amount of available nickel and how it is distributed. This is achieved by critical proteins that transport nickel ions in and out of cells, traffic nickel ions to where they are needed, and regulate the production of key factors. A major chemical challenge to these proteins is that their functions are controlled by nickel binding, which activates or inhibits the biochemical activities. How metal binding controls protein function is an intriguing fundamental question, and advancing our knowledge in this area requires examination of the bioinorganic chemistry of the metal complexes, analysis of the protein activities and structures, and knowledge of the broad contexts of these systems. This proposal describes experiments to uncover how nickel binding activates a functional response in crucial nickel homeostasis proteins. Our research to date has provided detailed information about the individual proteins and their nickel-binding activities. We are now at the exciting stage of being able to answer foundational questions about the mechanisms of the nickel-dependent activities of these systems. To achieve this goal, we will use an interdisciplinary approach that draws from protein chemistry, inorganic spectroscopy, and structural biology, providing a rich educational environment for trainees. Specific aims include delineating the relationship between metal ion coordination and DNA binding by a nickel responsive transcription factor, and also determining how this activity is connected to pH-dependent regulation. Furthermore, we will establish how metal complex binding is linked to metal-selective transport by a key nickel membrane importer. Metal-regulated activity is an essential property of proteins that manage different types of metal ions, not just nickel, so this program will help us achieve our ultimate objective, which is to learn the chemical mechanisms that govern intracellular transition metal homeostasis at a molecular level. Understanding this fundamental aspect of life will have a significant impact on areas such as biotechnology and environmental remediation. Finally, this multidisciplinary program is performed in an inclusive, supportive, and respectful setting, and provides excellent training in research, analysis, and communication. This education prepares highly skilled young scientists for future careers in a variety of industries including pharmaceutical, biotechnology, biomedical, as well as related areas.