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Mechanism of copper uptake from ceruloplasmin by cells and the involvement of an additional copper uptake transporter

Ceruloplasmin (Cp) is the most abundant copper‐containing protein in the blood plasma. Though well known for its ferroxidase activity, it also has other functions. We have now demonstrated it is a circulating source of copper for cells, using 64Cu‐labeled Cp purified from mouse plasma, and mouse embryonic fibroblasts (MEFs) that do and do not express the only as yet identified copper uptake transporter in mammalian cells, CTR1. During copper delivery, Cp was converted from the holo (Cu‐containing) to the apo form, as demonstrated by immunoblotting of native PAGE gels, and 64Cu‐uptake was not reduced by inhibitors of endocytosis. Uptake of Cp‐Cu was significantly greater in cells expressing vs not expressing Ctr1, indicating that Ctr1 can take up copper from Cp. However, most of the uptake was through an as yet unidentified transporter, that like Ctr1 preferred Cu(I) and was inhibited by Ag(I). Attempts to cross‐link Cp to this transporter in the Ctr1−/− MEFs did not result in the identification of plausible transporter proteins. To improve chances of cross‐linking sufficient protein for identification by MS‐MS, studies with plasma membrane fractions from brains and hearts of rats incubated at 4ºC with purified 67Cu‐labeled rat plasma Cp were initiated (a method used previously to identify Cp “receptors”; BBRC 139: 822, 1986) and Cp‐binding to the membranes was confirmed. We conclude that uptake of copper from Cp occurs at the cell surface, with formation of apoCp and delivery of the copper to Ctr1 and an additional transporter.