The long term goal of this project is to understand the molecular mechanisms of cooper homeostasis in humans in atomic detail. Copper is an essential element, serving as a cofactor for many key enzymes, but is also very reactive. How this potentially toxic metal ion is delivered to distinct cellular locations and particular proteins is not well understood. A new class of proteins which function in the intracellular delivery of copper to specific target proteins has recently been identified, however. These proteins, which are called copper chaperones, are linked to human diseases, including Menkes syndrome, Wilson disease, and familial amyotrophic lateral sclerosis (FALS), and are potential targets for new therapeutics. We are focusing on two different types of chaperones, proteins that shuttle copper through the cytosol to transport ATPases in the secretory pathway and proteins that delivery copper specifically to superoxide dismutase I (SOD1). The molecular mechanisms of copper trafficking between these cytosolic chaperones and their corresponding target proteins are not well understood.
The specific aims of this proposal are 1) to refine the high resolution X-ray structures of the Hg(II) and apo forms of Atx1, a yeast chaperone which mediates copper delivery to the transport ATPase Ccc2 and to solve the structure of the Cu(I) form, 2) to study interactions between Atx1 and Ccc2 and between the analogous human proteins Hah1 and the Menkes/Wilson proteins, 3) to solve the structure of the yeast SOD1 chaperone Lys7, 4) to crystallize and solve the structure of the human SOD1 chaperone Ccs, and 5) to study interactions between Lys7 or Ccs and SOD1. Our primary tool will be X-ray crystallography, but we will also pursue biochemical and biophysical approaches. Accomplishment of these specific aims will reveal the details of copper binding by these proteins, including stoichiometry and coordination geometry, and will elucidate how these chaperones interact with their cooper receptor proteins as well as features of the copper binding and protein-protein interactions which render each chaperone specific for its target protein. The proposed research will provide an important first step toward understanding human copper homeostasis on the molecular level, and is expected to impact the development of new therapeutics for diseases related to copper metabolism.
| Purohit, Rahul; Ross, Matthew O; Batelu, Sharon et al. (2018) Cu+-specific CopB transporter: Revising P1B-type ATPase classification. Proc Natl Acad Sci U S A 115:2108-2113 |
| Smith, Aaron T; Ross, Matthew O; Hoffman, Brian M et al. (2017) Metal Selectivity of a Cd-, Co-, and Zn-Transporting P1B-type ATPase. Biochemistry 56:85-95 |
| Ross, Matthew O; Rosenzweig, Amy C (2017) A tale of two methane monooxygenases. J Biol Inorg Chem 22:307-319 |
| Lawton, Thomas J; Kenney, Grace E; Hurley, Joseph D et al. (2016) The CopC Family: Structural and Bioinformatic Insights into a Diverse Group of Periplasmic Copper Binding Proteins. Biochemistry 55:2278-90 |
| Lawton, Thomas J; Rosenzweig, Amy C (2016) Methane-Oxidizing Enzymes: An Upstream Problem in Biological Gas-to-Liquids Conversion. J Am Chem Soc 138:9327-40 |
| Lawton, Thomas J; Rosenzweig, Amy C (2016) Biocatalysts for methane conversion: big progress on breaking a small substrate. Curr Opin Chem Biol 35:142-149 |
| Smith, Aaron T; Barupala, Dulmini; Stemmler, Timothy L et al. (2015) A new metal binding domain involved in cadmium, cobalt and zinc transport. Nat Chem Biol 11:678-84 |
| Kathman, Stefan G; Span, Ingrid; Smith, Aaron T et al. (2015) A Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic Mechanism. J Am Chem Soc 137:12442-5 |
| Smith, Aaron T; Smith, Kyle P; Rosenzweig, Amy C (2014) Diversity of the metal-transporting P1B-type ATPases. J Biol Inorg Chem 19:947-60 |
| Chang, Wei-chen; Guo, Yisong; Wang, Chen et al. (2014) Mechanism of the C5 stereoinversion reaction in the biosynthesis of carbapenem antibiotics. Science 343:1140-4 |
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