Morphological development and cytochrome <i>c</i> oxidase activity in <i>Streptomyces lividans</i> are dependent on the action of a copper bound Sco protein

<jats:p> Copper has an important role in the life cycle of many streptomycetes, stimulating the developmental switch between vegetative mycelium and aerial hyphae concomitant with the production of antibiotics. In streptomycetes, a gene encoding for a putative Sco-like protein has been identified and is part of an operon that contains two other genes predicted to handle cellular copper. We report on the Sco-like protein from <jats:italic>Streptomyces lividans</jats:italic> (Sco <jats:sup>Sl</jats:sup> ) and present a series of experiments that firmly establish a role for Sco <jats:sup>Sl</jats:sup> as a copper metallochaperone as opposed to a role as a thiol-disulphide reductase that has been assigned to other bacterial Sco proteins. Under low copper concentrations, a Δ <jats:italic>sco</jats:italic> mutant in <jats:italic>S. lividans</jats:italic> displays two phenotypes; the development switch between vegetative mycelium and aerial hyphae stalls and cytochrome <jats:italic>c</jats:italic> oxidase (CcO) activity is significantly decreased. At elevated copper levels, the development and CcO activity in the Δ <jats:italic>sco</jats:italic> mutant are restored to wild-type levels and are thus independent of Sco <jats:sup>Sl</jats:sup> . A CcO knockout reveals that morphological development is independent of CcO activity leading us to suggest that Sco <jats:sup>Sl</jats:sup> has at least two targets in <jats:italic>S. lividans</jats:italic> . We establish that one Sco <jats:sup>Sl</jats:sup> target is the dinuclear Cu <jats:sub>A</jats:sub> domain of CcO and it is the cupric form of Sco <jats:sup>Sl</jats:sup> that is functionally active. The mechanism of cupric ion capture by Sco <jats:sup>Sl</jats:sup> has been investigated, and an important role for a conserved His residue is identified. </jats:p>