The functions of Sco proteins from genome-based analysis

Sco proteins are widespread proteins found in eukaryotic as well as in many prokaryotic organisms. The 3D structure of representatives from human, yeast, and Bacillus subtilis has been determined, showing a thioredoxin-like fold. Sco proteins have been implicated mainly as copper transporters involved in the assembly of the CuA cofactor in cytochrome c oxidase. Some mutations have been identified in humans that lead to defective cytochrome c oxidase formation and thus to fatal illnesses. However, it appears that the physiological function of Sco proteins goes beyond assembly of the CuA cofactor. Extensive analysis of completely sequenced prokaryotic genomes reveals that 18% of them contain either Sco proteins but not CuA-containing proteins or vice versa. In addition, in several cases, multiple Sco-encoding genes occur even if only a single potential Sco target is encoded in the genome. Genomic context analysis indeed points to a more general role for Sco proteins in copper transport, also to copper enzymes lacking a CuA cofactor. To obtain further insight into the possible role of Sco in the assembly of other cofactors, a search for Cox11 proteins, which are important for CuB biosynthesis, was also performed. A general framework for the action of Sco proteins is proposed, based on the hypothesis that they can couple metal transport and thiol/disulfide-based oxidoreductase activity, as well as select between either of these two cellular functions. This model reconciles the variety of experimental observations made on these proteins over the years, and can constitute a basis for further studies.