Atox1 Contains Positive Residues that Mediate Membrane Association and Aid Subsequent Copper Loading
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Copper chaperones bind intracellular copper and ensure proper trafficking to downstream targets via protein–protein interactions. In contrast to the mechanisms of copper binding and transfer to downstream targets, the mechanisms of initial copper loading of the chaperones are largely unknown. Here, we demonstrate that antioxidant protein 1 (Atox1 in human cells), the principal cellular copper chaperone responsible for delivery of copper to the secretory pathway, possesses the ability to interact with negatively charged lipid headgroups via distinct surface lysine residues. Moreover, loss of these residues lowers the efficiency of copper loading of Atox1 in vivo, suggesting that the membrane may play a scaffolding role in copper distribution to Atox1. These findings complement the recent discovery that the membrane also facilitates copper loading of the copper chaperone for superoxide dismutase 1 and provide further support for the emerging paradigm that the membrane bilayer plays a central role in cellular copper acquisition and distribution.
KeywordsAtox1 Chaperone Copper trafficking Copper homeostasis Membrane scaffold
We would like to thank Dr Amy Rosenzweig for providing an Atox1 clone. We also are indebted to Dr Svetlana Lutsenko for the gift of the HEK293TREx cell line and a matched expression vector. This work was supported by NIH grant P01GM067166 (V.M.U.).
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