Copper (Cu) plays key catalytic and regulatory functions for biochemical reactions that are critical to normal growth, development and health. Menkes disease and Wilson's disease are two severe human genetic disorders of Cu metabolism that result in childhood mortality and hepatic and neurological dysfunction, respectively. Inappropriate copper balance is linked to myeloneuropathy, prion disease, Alzheimer's and cardiovascular disease and cancer. Consequently, it is critical to understand the mechanisms by which cells control the acquisition, distribution and utilization of Cu. While the identify and functions of the Cu import, intracellular distribution and efflux machinery are beginning to be understood, we know very little about the physiological role of the Ctr2 protein, the regulation of Cu import and how organisms establish global Cu homeostasis.
Three specific aims are outlined in this application, which are inter- related by the information they will decipher on the mechanisms of action of the mammalian Cu transport machinery and its regulation at the cellular and systemic level. In the first specific aim the physiological role of the mammalian Ctr2 protein in Cu acquisition will be ascertained through the analysis of mouse Ctr2 knock out mutants, through biochemical and cell biological experiments in cultured cells and through the analysis of Ctr2 mutant proteins. In the second specific aim the regulation of the Ctr1 Cu importer and the Ctr2 protein will be deciphered through an analysis of their post- translational regulation in cell culture. In the third specific aim experiments are outlined to identify a novel blood-borne signal that allows inter-organ communication between peripheral organs such as the heart and the copper acquisition and storage organs. Taken together, these investigations will decipher key functional roles and cellular and systemic regulatory mechanisms for the Cu acquisition machinery, the function of which is essential for normal growth, development and human health.

Public Health Relevance

Copper is an essential element for human health and the inability to properly regulate copper balance is associated with lethal childhood disease, liver and neurological disease, Alzheimer's disease, cardiovascular disease and cancer. The research outlined in this application is designed to understand how mammals properly acquire copper and how copper acquisition is regulated. These studies may identify pathways and potential therapeutic avenues that are important in human diseases of copper balance.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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Duke University
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Logeman, Brandon L; Thiele, Dennis J (2018) Reconstitution of a thermophilic Cu+ importer in vitro reveals intrinsic high-affinity slow transport driving accumulation of an essential metal ion. J Biol Chem 293:15497-15512
Logeman, Brandon L; Wood, L Kent; Lee, Jaekwon et al. (2017) Gene duplication and neo-functionalization in the evolutionary and functional divergence of the metazoan copper transporters Ctr1 and Ctr2. J Biol Chem 292:11531-11546
Öhrvik, Helena; Logeman, Brandon; Turk, Boris et al. (2016) Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain. J Biol Chem 291:13905-16
Srivastava, Shekhar; Panda, Saswati; Li, Zhai et al. (2016) Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1. Elife 5:
Öhrvik, Helena; Logeman, Brandon; Noguchi, Glyn et al. (2015) Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans. J Immunol 195:3654-64
Shawki, Ali; Anthony, Sarah R; Nose, Yasuhiro et al. (2015) Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese. Am J Physiol Gastrointest Liver Physiol 309:G635-47
García-Santamarina, Sarela; Thiele, Dennis J (2015) Copper at the Fungal Pathogen-Host Axis. J Biol Chem 290:18945-53
Allensworth, Jennifer L; Evans, Myron K; Bertucci, François et al. (2015) Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol Oncol 9:1155-68
Öhrvik, Helena; Thiele, Dennis J (2015) The role of Ctr1 and Ctr2 in mammalian copper homeostasis and platinum-based chemotherapy. J Trace Elem Med Biol 31:178-82
Ohrvik, Helena; Thiele, Dennis J (2014) How copper traverses cellular membranes through the mammalian copper transporter 1, Ctr1. Ann N Y Acad Sci 1314:32-41

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