The human copper chaperone for superoxide dismutase (hCCS) is a multi-domain metalloprotein responsible for delivering copper to cytoplasmic superoxide dismutase (SOD). hCCS contains three putative copper-binding domains, but their functional roles were initially unclear. Structural and mutagenesis studies demonstrate that hCCS forms a binuclear copper–sulfur cluster through its C-terminal Domain III, which mediates dimerization and copper transfer to SOD. While Domain I is capable of binding copper and may contribute to regulatory functions, Domain III is essential for hCCS activity. These findings clarify the molecular mechanism of copper delivery to SOD and define the functional specialization of hCCS domains.
