The Glass Bead Game: Domain Dynamics and Regulation of Copper Transporter ATP7B

Speaker

Oleg Dmitriev, University of Saskatchewan

Abstract

Copper is a co-factor of many proteins involved in respiration, hormone biosynthesis, connective tissue biogenesis, neuronal function, free radical detoxification and other biological processes, but free copper is toxic to the cell. To balance copper delivery to biosynthetic pathways and protection against copper toxicity, human cells possess a sophisticated copper transport system. ATP7B, also known as Wilson disease protein, is a key component of this system. ATP7B uses the energy of ATP hydrolysis to transport copper across the cell membranes.

Enzymatic activity and intracellular localization of ATP7B are regulated by copper. In the cell, copper, delivered by a chaperone protein Atox1, is transferred to the six cytosolic metal binding domains (MBD1-6) of ATP7B. Copper-dependent changes in the interactions and spatial orientation of the MBDs are thought to trigger relocalization of ATP7B between various cellular compartments, and activate copper export from the cell. Our lab studies the molecular mechanism of copper transport using nuclear magnetic resonance spectroscopy (NMR) and biochemical methods, Recombinant single-domain antibodies, or nanobodies, proved to be particularly useful tools to probe the dynamics or multidomain proteins by NMR. Our results show how domain dynamics regulates ATP7B activity and its localization in the cell.