Dmitriev Lab: Copper, Iron, Platinum and the Proteins that Handle them

Research Projects

ATP7B (Wilson disease protein) is a human copper transporter powered by ATP hydrolysis. ATP7B delivers copper to some proteins that use it as a cofactor, and also removes excess copper from the cell in a complex process that involves copper translocation across the lipid membrane and fusion of membrane vesicles with the plasma membrane. Activity of ATP7B is regulated by copper binding to six small and highly mobile cytosolic metal-binding domains, which are connected by flexible linkers. We use protein NMR spectroscopy to study how dynamics and interactions of the metal-binding domains signal activation of copper transport and direct ATP7B localization in the cell.

 

 

Cisplatin, carboplatin and oxaliplatin are platinum derivatives that are widely used to treat several common types of cancer. Cancer cells often develop resistance to platinum drugs and that undermines effectiveness of chemotherapy. We are investigating the role that copper transport proteins Atox1 and ATP7B play in cancer resistance to cisplatin and similar drugs. Our work has uncovered remarkable parallels between the pathways of copper and platinum transport in the cell.  Manipulating these pathways in cancer cells may increase effectiveness, and reduce toxicity of platinum anticancer drugs.

 
MEMO1 is a highly conserved protein, from yeast to humans, which is involved in many biological processes, including cancer cell motility and cancer metastasis, but its primary molecular function remains unknown. We have recently discovered that MEMO1 binds iron and copper and regulates iron homeostasis in the cell. Out goal is to understand the mechanism of iron regulation by MEMO1, the role of copper in its activity and the link between metal-dependent functions of MEMO1 and cancer metastasis.