期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：37
DOI：10.1073/pnas.2206905119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Since many proteins depend on copper ions for functionality, it is not surprising that cancer cells have a high demand for copper. Still, free copper ions are toxic as they can potentially catalyze the formation of harmful reactive oxygen species (ROS) upon coupling redox cycling between Cu(I) and Cu(II) with reduction of O
2. Here, we investigated copper binding to Memo1, an oncogenic protein linked to cancer. We demonstrate that Memo1 coordinates reduced but not oxidized copper ions, thereby preventing the copper ions from acting as redox catalysts for ROS generation. As Memo1 is a putative target for the treatment of cancer, it is of importance to identify its binding partners (e.g., metal ions) and the functional consequences of such interactions.
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.
