Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B

Significance Wilson disease is a disorder of copper homeostasis caused by mutations in ATP7B . The most frequent mutation of ATP7B results in an H1069Q substitution that affects the localization and stability of the protein product. By interrogating the interactome of ATP7B-H1069Q, we found that this mutant shows stronger interaction with HSP70, which drives mutant degradation. Using an HSP70 inhibitor for structural similarity searches, we identified a Food and Drug Administration-approved drug that increases ATP7B-H1069Q stability in cells and thus improves ATP7B function. This pharmacoproteomic strategy provides an effective shortcut from understanding cellular mechanisms operating in Wilson disease to rapid identification of safe pharmacological tools and therefore might be expanded for drug repurposing to counteract other genetic disorders.