Copper is an essential nutrient that serves as a co-factor for enzymes involved 
in critical cellular processes including energy generation, peptide hormone 
maturation, oxidative stress protection, and iron homeostasis. Although genes 
have been identified from yeast and mammals encoding a homologous subunit of a 
plasma membrane high affinity copper transporter, the presence of additional 
subunits that function as part of a copper transport complex has not been 
reported. We observed that ctr4(+), a previously identified copper transport 
protein from the fission yeast Schizosaccharomyces pombe, fails to complement 
bakers' yeast cells defective in high affinity copper transport and fails to be 
targeted to the plasma membrane. However, selection for S. pombe genes, which, 
when co-expressed with Ctr4, confer high affinity copper transport to S. 
cerevisiae cells resulted in the identification of ctr5(+). Both Ctr4 and Ctr5 
are integral membrane proteins, are co-regulated by copper levels and the 
copper-sensing transcription factor Cuf1, physically associate in vivo, are 
interdependent for secretion to the plasma membrane, and are each essential for 
high affinity copper transport. These studies in S. pombe identify Ctr4 and Ctr5 
as components of a novel eukaryotic heteromeric plasma membrane complex that is 
essential for high affinity copper transport.