Memo1 binds reduced copper ions, interacts with copper chaperone Atox1, and protects against copper-mediated redox activity in vitro

• DOI: 10.1073/pnas.2206905119
• Publication Date: 2022-09-06T17:57:56Z
• Authors: Xiaolu Zhang; Gulshan R. Walke; Istvan Horvath; Ranjeet Kumar; Stéphanie Blockhuys; Stellan Holgersson; Paul H. Walton; Pernilla Wittung-...
• Keywords: Ions; Models, Molecular; 0303 health sciences; Intracellular Signaling Peptides and Proteins; Biological Sciences; 3. Good health; Metallochaperones; 03 medical and health sciences; Copper Transport Proteins; Cell Line, Tumor; Humans; Reactive Oxygen Species; Oxidation-Reduction; Copper; Molecular Chaperones; Protein Binding

The protein mediator of ERBB2-driven cell motility 1 (Memo1) is connected to many signaling pathways that play key roles in cancer. Memo1 was recently postulated to bind copper (Cu) ions and thereby promote the generation of reactive oxygen species (ROS) in cancer cells. Since the concentration of Cu as well as ROS are increased in cancer cells, both can be toxic if not well regulated. Here, we investigated the Cu-binding capacity of Memo1 using an array of biophysical methods at reducing as well as oxidizing conditions in vitro. We find that Memo1 coordinates two reduced Cu (Cu(I)) ions per protein, and, by doing so, the metal ions are shielded from ROS generation. In support of biological relevance, we show that the cytoplasmic Cu chaperone Atox1, which delivers Cu(I) in the secretory pathway, can interact with and exchange Cu(I) with Memo1 in vitro and that the two proteins exhibit spatial proximity in breast cancer cells. Thus, Memo1 appears to act as a Cu(I) chelator (perhaps shuttling the metal ion to Atox1 and the secretory path) that protects cells from Cu-mediated toxicity, such as uncontrolled formation of ROS. This Memo1 functionality may be a safety mechanism to cope with the increased demand of Cu ions in cancer cells.