This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The mechanisms by which organisms control transition metal ions and the roles of these metals in cellular regulation have emerged as key areas of investigation in metallobiochemistry. Specific metal binding and responses are required by biological systems in order to avoid cross-talk between metals in the expression of proteins, in the uptake of specific metals, and for the incorporation of the correct metal into enzyme active sites. The details of how the metalloproteins recognize, bind and respond to the presence of the requisite metal ion are not well established. This is particularly true for transition metal ions, many of which have similar charges and ionic radii. Thus, it seems likely that coordination geometry and ligand preferences play important roles in distinguishing transition metals. The overall objective of this research project is to understand the structural parameters that underlie metal-specific binding, and the related protein structural responses to specific metal binding, in metalloproteins involved in metal trafficking. Toward this goal, we plan to use XAS to examine the structures of Ni sites in nickel trafficking proteins including: a metalloregulator (NikR), a metallotransporter (NikABCDE) and a metallochaperone (HypA)--proteins all involved in nickel trafficking in E. coli, and their homologs in H. pylori. The viability of bacteria, including human pathogens (like H. pylori), is linked to the acquisition of required metals (including Ni), and several human diseases have been shown to result from a breakdown in metal trafficking (e.g., Wilson's and Menkes diseases for copper, genetic hemochromatosis and other hereditary iron overload disorders for iron). In addition, a detailed understanding of the structural parameters involved in metal-trafficking may lead to new antibiotics that interfere with bacterial metal metabolism, which is frequently essential for pathogenesis, and the development of plants that are resistant to metals and useful in bioremediation.
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