Novel biochemical pathway for copper-metalloprotein biogenesis
Cytochrome oxidase, an essential enzyme for cellular respiration, carries a di-copper cofactor CuA that undergoes reversible redox switching during oxygen reduction. The hitherto unknown mechanism of CuA assembly is now reported in a "Science Advances" paper by Canonica et al. (Glockshuber group plus ETH collaborators).
The target protein for CuA insertion is cytochrome oxidase subunit II (CoxB). Two so-called metallochaperones are involved in copper delivery to CoxB: The Cu2+ specific chaperone ScoI, and PcuC, a metalloprotein binding one Cu1+ and one Cu2+ ion. CuA synthesis proceeds in three consecutive steps: (1) ScoI-Cu2+ associates with CoxB to a copper-bridged complex (ScoI-Cu2+-CoxB). (2) This complex is resolved by the delivery of Cu2+ from copper-loaded PcuC, resulting in the release of CoxB-Cu2+. (3) A second equivalent of copper-loaded PcuC then delivers Cu1+ to CoxB-Cu2+ to complete the synthesis of the CuA center in CoxB, in which the two copper ions assume a mixed-valence Cu1.5+-Cu1.5+ state. Important aspects of the newly discovered pathway might be conserved from bacteria to humans. This is a fine example showing the crucial role of copper transfer proteins that eliminate toxic, free-floating copper ions in the cell.
Link to the publication in external pageScience Advances.