Copper is essential for life and, not surprisingly, imbalances in copper homeostasis contribute to the progression of many neurodegenerative diseases including Alzheimer's, Creutzfeldt-Jakob and Parkinson's disease. The Copper Uptake transporter (CTR) family of proteins, identified in a variety of eukaryotic organisms, including humans, is required for the cellular uptake of this essential metal ion. Despite its physiological importance, however, it is still unclear how copper is taken up through CTR proteins and how a hazardous accumulation of free copper in the cytosol is prevented. I hypothesize that the human CTR protein (hCTR1) has evolved to accomplish both tasks by first trapping copper after uptake and then handing it off directly to copper chaperone proteins for intracellular distribution.
My specific aims are designed to test this hypothesis by solving the 3D structure of hCTR1 (Aim 1) and to determine if and how the transporter and chaperone proteins interact to accomplish copper uptake (Aim 2). The expected results will be milestones in the understanding of copper homeostasis and could help in designing new therapeutics for the treatment of a wide assortment of neurodegenerative diseases. ? ? ?
|Pope, Christopher R; De Feo, Christopher J; Unger, Vinzenz M (2013) Cellular distribution of copper to superoxide dismutase involves scaffolding by membranes. Proc Natl Acad Sci U S A 110:20491-6|
|De Feo, Christopher J; Mootien, Sara; Unger, Vinzenz M (2010) Tryptophan scanning analysis of the membrane domain of CTR-copper transporters. J Membr Biol 234:113-23|
|De Feo, Christopher J; Aller, Stephen G; Siluvai, Gnana S et al. (2009) Three-dimensional structure of the human copper transporter hCTR1. Proc Natl Acad Sci U S A 106:4237-42|
|De Feo, Christopher J; Aller, Stephen G; Unger, Vinzenz M (2007) A structural perspective on copper uptake in eukaryotes. Biometals 20:705-16|