Human copper homeostasis: a network of interconnected pathways

Abstract

Copper plays an essential role in normal human physiology. Copper misbalance affects heart development, CNS and liver function, influences lipid metabolism, inflammation, and resistance to chemotherapeutic drugs. Recent studies yielded new information on the structure, function, and regulation of human copper transporters, uncovered unanticipated functions for copper chaperones, and established connections between copper homeostasis and other metabolic pathways. It has become apparent that the copper trafficking machinery is regulated at several levels and that the cross-talk between cell compartments contributes to the intracellular copper balance. The human copper regulon is emerging.

Figure 1

Copper distribution pathways in a generalized mammalian cell. CTR1 accepts cooper from the extracellular copper carriers and transfers copper into cytosol; changes in copper levels induce reversible trafficking between the plasma membrane and intracellular vesicles. CTR2 is predominantly intracellular but can be found at the plasma membrane. Entering copper is either binds directly or is retrieved from CTR1/CTR2 by copper chaperones that have multiple functions; CCS distributes copper to SOD1 in cytosol and mitochondria, while Atox1 transfers copper to the secretory pathway and nucleus. An ensemble of proteins regulates copper delivery to cytochrome c oxidase (CCO) in mitochindria. Cu-ATPases transport copper to the secretory pathways for incorporation into cuproenzumes and mediate copper excretion by sequestering excess copper in vesicles. The trafficking of Cu-ATPases between these two locations is associated with phosphorylation by a kinase (indicated by stars), which increases in response to copper elevation.

Figure 2

Structural comparison of human Atox1 (blue, 1TL5) and Domain I of CCS (green, 2CRL). Sequence alignment illustrates significant similarity of mammalian Atox1 and CCS (identical residues are in red, conserved residues in orange). The conserved residues around the metal-binding site are highlighted by grey (top); their location in the superimposed structures (left) and surface exposure (right) are shown (bottom).