2.A.6.1.4
Cu⁺ /Ag⁺ efflux pump, CusABCF (may pump ions from the periplasm to the external medium); CusF is a periplasmic Cu⁺ /Ag⁺ binding receptor essential for full resistance (Franke et al., 2003). Bagai et al. (2007) reported that CusB (MFP) binds one molecule of Ag⁺ or Cu⁺ via four conserved methionines and induces a substrate-linked conformational change (Bagai et al., 2007). The crystal structures of CusB are available (Su et al., 2009). The crystal structure of the CusAB complex has been solved (PDB# 3K07) (Su et al., 2011a). CusC is listed under TC# 1.B.17.3.5. The metal-binding methionines play a role in restricting the substrates to monovalent heavy metals (Conroy et al., 2010). It has been reported to export L-cysteine (Yamada et al., 2006). Crystal structures of the CusA efflux pump suggested that methionine residues in a 3-methionine cluster, bind the metal as a transport intermediate (Long et al., 2010). Four methionine pairs in the transmembrane region, and one in the periplasmic domain may comprise the channel. Cu⁺ is exported from the cytoplasm to the periplasmic chaparone, CusF in the extracellular space (Padilla-Benavides et al. 2014). The Cus efflux system removes Cu⁺ and Ag⁺ from both the cell cytoplasm and the periplasm (Su et al., 2011b; Delmar et al. 2014). Metal-bound CusB is required for activation of Cu⁺ transfer from CusF directly to a site in the CusA antiporter (Chacón et al. 2014). Metal transfer occurs between CusF and apo-CusB, and when metal-loaded, CusB plays a role in the regulation of metal ion transfer from CusF to CusA in the periplasm.  The ratio of CusA (RND):CusB (MFP):CusC (OMF) is 3:6:3 (Delmar et al. 2013). Intermediates in metal transfer reactions have been measured (Chacón et al. 2018).