Grant: Operating Grant - PA: Regional Partnership Program - Saskatchewan

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 protein (ATP7B) and Menkes disease protein (ATP7A) regulate copper concentration in the cell and deliver copper to biosynthetic pathways. These enzymes are targets of many mutations that cause severe metabolic disorders. Importantly, ATP7B and ATP7A are involved in cancer resistance to platinum-based chemotherapeutic drugs. To understand the critical steps in the activity cycle of the copper transporters, we will investigate the structure, molecular motions and interactions of the isolated domains, or functional modules, of the Wilson disease protein 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-transporters and analyze the structural basis of several frequent disease causing mutations. Using synchrotron radiation, NMR, and biochemical techniques, we will investigate mechanism of cancer resistance to platinum-based anticancer drugs associated with ATP7B and ATP7A. 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. Structural information on Wilson disease protein will facilitate design of the new inhibitors and modulators of copper transporters, which will help to overcome certain types of drug resistance in cancer.