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Sco proteins are present in all types of organisms, including the vast major-ity of eukaryotes and many prokaryotes. It is well established that Sco pro-teins in eukaryotes are involved in the assembly of the CuAcofactor of mitochondrial cytochromecoxidase; however their precise role in this pro-cess has not yet been elucidated at the molecular level. | ễFEBS Journal REVIEW ARTICLE Seeking the determinants of the elusive functions of Sco proteins Lucia Banci1 2 Ivano Bertini1 2 Gabriele Cavallaro1 and Simone Ciofi-Baffoni1 2 1 Magnetic Resonance Center CERM University of Florence Italy 2 Department of Chemistry University of Florence Italy Keywords copper cytochrome c oxidase redox Sco thiol-disulfide Correspondence I. Bertini Magnetic Resonance Center University of Florence Via Luigi Sacconi 6 50019 Sesto Fiorentino Italy Fax 39 055 457 4271 Tel 39 055 457 4272 E-mail ivanobertini@cerm.unifi.it Received 15 February 2011 revised 12 April 2011 accepted 18 April 2011 doi 10.1111 j.1742-4658.2011.08141.x Sco proteins are present in all types of organisms including the vast majority of eukaryotes and many prokaryotes. It is well established that Sco proteins in eukaryotes are involved in the assembly of the CuA cofactor of mitochondrial cytochrome c oxidase however their precise role in this process has not yet been elucidated at the molecular level. In particular some but not all eukaryotes including humans possess two Sco proteins whose individual functions remain unclear. There is evidence that eukaryotic Sco proteins are also implicated in other cellular processes such as redox signalling and regulation of copper homeostasis. The range of physiological functions of Sco proteins appears to be even wider in prokaryotes where Sco-encoding genes have been duplicated many times during evolution. While some prokaryotic Sco proteins are required for the biosynthesis of cytochrome c oxidase others are most likely to take part in different processes such as copper delivery to other enzymes and protection against oxidative stress. The detailed understanding of the multiplicity of roles ascribed to Sco proteins requires the identification of the subtle determinants that modulate the two properties central to their known and potential functions i.e. copper binding and redox properties. In this review we provide a .