Disease mechanisms of copper chaperone Atox1

Research Project, 2020 – 2024

Copper is an essential metal ion that provides functionality to many human enzymes. Disruption in transport and delivery of copper ions, perturbing cellular copper homeostasis, are observed in a variety of diseases, such as Wilson disease, Parkinson’s disease and cancer. To reveal the role of copper in these diseases, one must identify and acquire an understanding of the copper-dependent protein-protein interactions that are at play.

Recent discoveries have shown the cytoplasmic copper chaperone Atox1 to play a key role in all three diseases. To reach the molecular-mechanistic level, we will apply strategic protein engineering in combination with biophysical methods, activity assays and cell studies to address three aims. The project objectives are to reveal structural, thermodynamic and functional principles for (aim 1) the role of Wilson disease mutations in Atox1’s target protein ATP7B for copper acceptance and domain-domain interactions, (aim 2) the consequences of Atox1 interactions with Parkinson’s disease protein, alpha-synuclein, for amyloid formation and (aim 3) how Atox1 interacts with, and delivers copper to, the copper-dependent, cancer-promoting enzyme Memo, along with consequences on cell migration.

This original research will provide fundamental information on Atox1’s functional repertoire and identify pathways/complexes that that may be targets for new therapeutic approaches.