This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Copper is required for the activity of many enzymes involved in respiration, neuron function, formation of connective tissue, endocrine processes, and radical detoxification in the human body. Wilson disease ATPase and Menkes disease ATPase regulate copper concentration in the cell and deliver copper to biosynthetic pathways. These proteins are targets of many mutations that cause severe metabolic disorders. Importantly, Wilson and Menkes ATPases are involved in cancer resistance to platinum- based chemotherapeutic drugs. To understand the critical steps in the activity cycle of the copper ATPases, we will investigate the structure, molecular motions and interactions of the isolated domains, or functional modules, of the Wilson and Menkes proteins using multidimensional Nuclear Magnetic Resonance (NMR), a technique uniquely suited for studying protein structure and dynamics in solution. We will trace the sequence of molecular events involved in substrate binding by copper-transporting ATPases and analyze the structural basis of several frequent disease causing mutations. To trace the pathway of copper in Wilson and Menkes disease ATPases, we will attempt to map the copper-binding site in the cell membrane. This work is expected to improve the understanding of an important class of transport proteins and provide a new insight into the molecular basis of the disorders of copper metabolism. Structures of the individual domains of Wilson and Menkes ATPase will facilitate design of the new inhibitors and modulators of these enzymes, which may help to overcome certain types of drug resistance in cancer.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR002301-26
Application #
8361162
Study Section
Special Emphasis Panel (ZRG1-BCMB-H (40))
Project Start
2011-03-01
Project End
2012-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
26
Fiscal Year
2011
Total Cost
$1,579
Indirect Cost
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Selen Alpergin, Ebru S; Bolandnazar, Zeinab; Sabatini, Martina et al. (2017) Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine. Physiol Rep 5:
Didychuk, Allison L; Montemayor, Eric J; Carrocci, Tucker J et al. (2017) Usb1 controls U6 snRNP assembly through evolutionarily divergent cyclic phosphodiesterase activities. Nat Commun 8:497
Ting, See-Yeun; Yan, Nicholas L; Schilke, Brenda A et al. (2017) Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23. Elife 6:
Bhute, Vijesh J; Bao, Xiaoping; Dunn, Kaitlin K et al. (2017) Metabolomics Identifies Metabolic Markers of Maturation in Human Pluripotent Stem Cell-Derived Cardiomyocytes. Theranostics 7:2078-2091
Mong, Surin K; Cochran, Frank V; Yu, Hongtao et al. (2017) Heterochiral Knottin Protein: Folding and Solution Structure. Biochemistry 56:5720-5725
Handley, Lindsey D; Fuglestad, Brian; Stearns, Kyle et al. (2017) NMR reveals a dynamic allosteric pathway in thrombin. Sci Rep 7:39575
Dias, Andrew D; Elicson, Jonathan M; Murphy, William L (2017) Microcarriers with Synthetic Hydrogel Surfaces for Stem Cell Expansion. Adv Healthc Mater 6:
Zhang, Fan; Barns, Kenneth; Hoffmann, F Michael et al. (2017) Thalassosamide, a Siderophore Discovered from the Marine-Derived Bacterium Thalassospira profundimaris. J Nat Prod 80:2551-2555
Nguyen, Eric H; Daly, William T; Le, Ngoc Nhi T et al. (2017) Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion. Nat Biomed Eng 1:
Bhute, Vijesh J; Ma, Yan; Bao, Xiaoping et al. (2016) The Poly (ADP-Ribose) Polymerase Inhibitor Veliparib and Radiation Cause Significant Cell Line Dependent Metabolic Changes in Breast Cancer Cells. Sci Rep 6:36061

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