Extrinsic and intrinsic factors affect copper‐induced protein precipitation across eukaryotic and prokaryotic proteomes

The susceptibility of a protein to aggregation upon exposure to copper ions (Cu) has been recognized as a contributor to Cu-induced cellular dysfunction and toxicity. Different cell types succumb to Cu to varying degrees, indicating innate differences between species in the mechanisms used to tolerate exposure to Cu in excess of their biological needs. Investigated here are properties associated with metal-induced protein precipitation (MiPP) compared across cell lysates generated from three cell lines from three different species: Escherichia coli, Candida albicans, and the human prostate cancer cell line 22Rv1. The human cell line was the most sensitive to Cu-induced protein precipitation, while C. albicans was the most tolerant. This trend aligns with the relative susceptibilities of these cells to Cu-induced cytotoxicity. The unique susceptibilities of these proteomes to precipitation by Cu were examined to identify factors that influence a protein's relative sensitivity to this effect. Identified were intrinsic factors such as frequency and solvent accessibility of known metal-binding amino acids, as well as external factors related to the molecular composition of their native cell lysates. Overall, our findings help to elucidate the biomolecular basis underpinning the unique capacity of adventitious Cu to have differential effects on eukaryotic and prokaryotic organisms and the level of Cu needed to induce protein precipitation.