Ortholog search of proteins involved in copper delivery to cytochrorne c oxidase and functional analysis of paralogs and gene neighbors by genomic context

Cytochrome c oxidase (COX) is a multi-subunit enzyme of the mitochondrial respiratory chain. Delivery of metal cofactors to COX is essential for assembly, which represents a long-standing puzzle. The proteins Cox17, Sco1/2, and Cox11 are necessary for copper insertion into CUA and CUB redox centers of COX in eukaryotes. A genome-wide search in all prokaryotic genomes combined with genomic context reveals that only Sco and Cox11 have orthologs in prokaryotes. However, while Cox11 function is confined to COX assembly, Sco acts as a multifunctional linker connecting a variety of biological processes. Multifunctionality is achieved by gene duplication and paralogs. Neighbor genes of Sco paralogs often encode cuproenzymes and cytochrome c domains and, in some cases, Sco is fused to cytochrome c. This led us to suggest that cytochrome c might be relevant to Sco function and the two proteins might jointly be involved in COX assembly. Sco is also related, in terms of gene neighborhood and phylogenetic occurrence, to a newly detected protein involved in copper trafficking in bacteria and archaea, but with no sequence similarity to the mitochondrial copper chaperone Cox17. By linking the assembly system to the copper uptake system, Sco allows COX to face alternative copper trafficking pathways.