Crystal Structure of the Human Copper Chaperone ATOX1 Bound to Zinc Ion

The bioavailability of copper (Cu) in human cells may depend on a complex interplay with zinc (Zn) ions. We investigated the ability of the Zn ion to target the human Cu-chaperone Atox1, a small cytosolic protein capable of anchoring Cu(I), by a conserved surface-exposed Cys-X-X-Cys (CXXC) motif, and deliver it to Cu-transporting ATPases in the trans-Golgi network. The crystal structure of Atox1 loaded with Zn displays the metal ion bridging the CXXC motifs of two Atox1 molecules in a homodimer. The identity and location of the Zn ion were confirmed through the anomalous scattering of the metal by collecting X-ray diffraction data near the Zn K-edge. Furthermore, soaking experiments of the Zn-loaded Atox1 crystals with a strong chelating agent, such as EDTA, caused only limited removal of the metal ion from the tetrahedral coordination cage, suggesting a potential role of Atox1 in Zn metabolism and, more generally, that Cu and Zn transport mechanisms could be interlocked in human cells.

Automated summary

The bioavailability of copper in human cells may be influenced by the presence of zinc ions. This study demonstrates that zinc ions can target the Cu-chaperone Atox1 and deliver it to Cu-transporting ATPases. The crystal structure of Atox1 loaded with zinc confirms the presence and location of the zinc ion. These findings suggest a potential interplay between Cu and Zn transport mechanisms in human cells.