Copper is an important element in host-microbe interactions, acting both as a catalyst in enzymes and as a potential toxin.
INTRODUCTIONThe influence of Cu + distribution in the outcome of hostbacteria interactions is becoming increasingly evident (Argüello et al., 2011;Hodgkinson & Petris, 2012;Samanovic et al., 2012). Toward preventing bacterial proliferation, compartmental 'flooding' of potentially deleterious metals such as Cu + has been observed in infected phagosomes and in the xylem of plants (Hodgkinson & Petris, 2012;Wagner et al., 2005;Yuan et al., 2010). Cu + toxicity through Fenton-like reactions, and as a competitor at cognate metals sites in proteins or affecting Fe-S clusters of hydratases and isomerases, is well established (Macomber & Imlay, 2009;Stohs & Bagchi, 1995). As a consequence, to manage elevated cytoplasmic Cu + , infectious bacteria have evolved sophisticated mechanisms of metal sensing and detoxification. These consist of at least a Cu + -responsive transcription factor, a Cu + -binding chaperone and a transmembrane (TM) Cu + transporting P-type ATPase (Dupont et al., 2011;Rademacher & Masepohl, 2012). Copper is also required for metallation of various cuproenzymes, such as cytochrome c oxidases (Coxs), Cu/Zn superoxide dismutases (Cu/Zn-Sods), laccases, tyrosinases, nitrite reductases, methane monooxygenases, NADH dehydrogenase 2, Cu + -dependent amine oxidases and Cu + -dependent polysaccharide oxygenases (Argüello et al., 2013;Rensing & McDevitt, 2013;Ridge et al., 2008). Some of these enzymes are necessary for virulence, as they either prevent the toxicity of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Lynch & Kuramitsu, 2000;Philippot, 2005), or are part of the respiratory electron transport chain (Preisig et al., 1996b). Given, then, that these proteins are located in distinct compartments (plasma membrane, periplasm or secreted into the media), Cu + distribution for metalloprotein assembly also appears critical for bacterial survival (Argüello et al., 2011;Waldron & Robinson, 2009 (Argüello, 2003; Argüello et al., 2007). Enzymatic studies have shown the common transport mechanism, kinetic features, substratebinding stoichiometry and direction of transport, i.e. cytoplasmic Cu + efflux (Argüello et al., 2007(Argüello et al., , 2011. The highresolution (3.2 Å ) crystal structure of the Legionella pneumophila Cu + -ATPase CopA revealed the architecture of TMs, the chaperone-docking platform and ligandexchanging-invariant residues at the cytoplasmic interphase (Gourdon et al., 2011;Padilla-Benavides et al., 2013). From a physiological point of view, prokaryotic Cu + -ATPases have been associated typically with maintaining low intracellular Cu + levels (Argüello et al., 2007;Osman & Cavet, 2008;Solioz et al., 2010). However, the presence of multiple Cu + -ATPases in a given organism challenges the idea of a singular and redundant function for these enzymes (Argüello et al., 2011), albeit the possibility of alternative function does appear counterintuit...