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 is 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 (at least among the ligands provided by amino acids) play important roles in distinguishing transition metals. This proposal seeks to use biophysical methods aimed at delineating structural parameters that are involved in determining metal specificity. 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 examine the structural parameters involved in a metalloregulator (NikR), a metallotransporter (NikABCDE) and a metallochaperone (HypB)--proteins all involved in nickel trafficking in E. coli. The viability of bacteria, including human pathogens, is linked to the acquisition of required metals, 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). A detailed understanding of metal trafficking is thus important to understanding metal metabolism and its effect on human health, and requires an understanding of mechanisms by which metalloregulators, metal transporters and chaperones specific to each required metal operate. In addition, a detailed understanding of the structural parameters involved in metal-trafficking may lead to the design of 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM069696-01A1
Application #
6820419
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Preusch, Peter C
Project Start
2004-09-15
Project End
2008-07-31
Budget Start
2004-09-15
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$207,214
Indirect Cost
Name
University of Massachusetts Amherst
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Maroney, Michael J; Hondal, Robert J (2018) Selenium versus sulfur: Reversibility of chemical reactions and resistance to permanent oxidation in proteins and nucleic acids. Free Radic Biol Med 127:228-237
Hu, Heidi Q; Huang, Hsin-Ting; Maroney, Michael J (2018) The Helicobacter pylori HypA·UreE2 Complex Contains a Novel High-Affinity Ni(II)-Binding Site. Biochemistry 57:2932-2942
Glauninger, Hendrik; Zhang, Yifan; Higgins, Khadine A et al. (2018) Metal-dependent allosteric activation and inhibition on the same molecular scaffold: the copper sensor CopY from Streptococcus pneumoniae. Chem Sci 9:105-118
Huang, Hsin-Ting; Bobst, Cedric E; Iwig, Jeffrey S et al. (2018) Co(II) and Ni(II) binding of the Escherichia coli transcriptional repressor RcnR orders its N terminus, alters helix dynamics, and reduces DNA affinity. J Biol Chem 293:324-332
Hu, Heidi Q; Johnson, Ryan C; Merrell, D Scott et al. (2017) Nickel Ligation of the N-Terminal Amine of HypA Is Required for Urease Maturation in Helicobacter pylori. Biochemistry 56:1105-1116
Martin-Diaconescu, Vlad; Joseph, Crisjoe A; Boer, Jodi L et al. (2017) Non-thiolate ligation of nickel by nucleotide-free UreG of Klebsiella aerogenes. J Biol Inorg Chem 22:497-503
Carr, Carolyn E; Foster, Andrew W; Maroney, Michael J (2017) An XAS investigation of the nickel site structure in the transcriptional regulator InrS. J Inorg Biochem 177:352-358
Blum, Faith C; Hu, Heidi Q; Servetas, Stephanie L et al. (2017) Structure-function analyses of metal-binding sites of HypA reveal residues important for hydrogenase maturation in Helicobacter pylori. PLoS One 12:e0183260
Carr, Carolyn E; Musiani, Francesco; Huang, Hsin-Ting et al. (2017) Glutamate Ligation in the Ni(II)- and Co(II)-Responsive Escherichia coli Transcriptional Regulator, RcnR. Inorg Chem 56:6459-6476
Denby, Katie J; Iwig, Jeffrey; Bisson, Claudine et al. (2016) The mechanism of a formaldehyde-sensing transcriptional regulator. Sci Rep 6:38879

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