Physiological roles of a new copper-binding protein : relationship between new copper-binding protein and hereditary copper

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Cu is an essential trace element which requires a delicate cellular balance between a necessary concentration and toxicity. Metallothionein (MT), a low molecular weight heavy-binding protein, plays an important role in Cu homeostasis and detoxification. In this study, the Cu-binding low molecular weight proteins induced by single or multiple Cu-injection rats were identified as Cu-MTs and/or a new Cu-binding protein using a new purification procedure of both of the new protein and Cu-MT under the aerobic condition.There were many debate on the existence of MT and other Cu-binding proteins which appeared in tissues of Cu-loaded animals. We settled the confusion by demonstrating of the presence of a new Cu-induced protein which did not belong to MT group, because the protein was a low cystein content and bound two Cu atoms per a molecule. We did show that only Cu-MT was induced by a single injection of Cu in rat liver and both of Cu-MT and the new protein appeared by the multiple injections of Cu. This result suggests that new protein was synthesized by excessive Cu which was not sufficiently detoxified by Cu-MT to serve detoxification of Cu when the hepatic Cu content increased and reached a certain threshold value.In addition, we established that excess amounts of Cu in the kidney of Macular mice, a model for Menke's disease (X-linked disorder of Cu metabolism), were found as Cu-MT. The Cu-MT was predominant in the proximal convoluted tubule cells of the cortex. MT mRNA was also observed in the cortex, indicating that the protein was biosynthesized in this region. On the other hand, the new Cu-binding protein was hardly detected in the kidney of macular mice. From these results the new protein was considered to play a key role in Cu-metabolism.