Metal Selectivity of Nickel Metalloproteins

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My research program will examine the chemical properties and activities of cellular proteins that handle nickel. Nickel is an essential nutrient for many forms of life, but this metal can also be toxic if the distribution and accumulation is not controlled. For this reason, the organisms that need nickel have many types of proteins that ensure the safe use of the metal ion. These proteins must be selective for nickel in the presence of other types of physiologically-relevant metal ions but it is not clear how metal selectivity is achieved. This is an intriguing fundamental problem that requires a detailed study of the bioinorganic chemistry, biochemical activities, and structures of the proteins involved, as well as knowledge about the biological context of these systems. Our research to date has provided detailed information about the individual components of the nickel pathways. We are now at the exciting stage of building on what we have learned to address central issues about these systems.This proposal describes experiments to study how metal selectivity is realized in key nickel homeostasis proteins. We will define the coordination environments around the different types of metals, and how they impact the structures and activities of the proteins. These goals will be achieved by using an interdisciplinary approach that draws from biochemistry, inorganic spectroscopy, and structural biology, providing a rich educational environment for trainees. Specific goals include delineating the relationship between metal-selective coordination and modulation of enzymatic activity in several GTPase proteins. We will also structurally define the metal complexes of a high-affinity metal-binding sequence and determine if there is metal-selective control of the function of this site. Furthermore, we will generate a genetically-encoded nickel sensor to address the question of how much intracellular metal is available and how this changes in response to shifts in the metabolism and/or environment of the organism, a critical aspect of nickel homeostasis. 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, a fundamental aspect of life. Understanding this challenging problem will have significant impact on areas such as biotechnology, medicine, and environmental remediation.