3.A.3.5.5
Cu⁺, Ag⁺-ATPase (efflux) (Fan and Rosen, 2002).  There are two metal binding domains (MBDs). The distal N-terminal MBD1 possesses a function analogous to the metallochaperones of related prokaryotic copper resistance systems and is involved in copper transfer to the membrane-integral ion binding sites of CopA. In contrast, the proximal domain MBD2 has a regulatory role by suppressing the catalytic activity of CopA in the absence of copper (Drees et al. 2015). The functions of Me²⁺ exporters are often supported by chaperone proteins, which scavenge the metal ions from the cytoplasm. A CopA chaperone is expressed in E. coli from the same gene that encodes the transporter (Meydan et al. 2017). Some ribosomes translating copA undergo programmed frameshifting, terminate translation in the -1 frame, and generate the 70 aa-long polypeptide CopA(Z), which helps cells survive toxic copper concentrations. The high efficiency of frameshifting is achieved by the combined stimulatory action of a "slippery" sequence, an mRNA pseudoknot, and the CopA nascent chain. Similar mRNA elements are not only found in the copA genes of other bacteria but are also present in ATP7B, the human homolog of copA, and direct ribosomal frameshifting in vivo (Meydan et al. 2017). Cu(i) (Cu⁺) pumps, of which CopA is an example, are primary-active electrogenic uniporters. The Cu⁺ translocation cycle does not require proton counter-transport, resulting in electrogenic generation of a transmembrane potential upon translocation of one Cu⁺ per ATP hydrolysis in the catalytic cycle (Abeyrathna et al. 2020).  Extracellular vesicle formation provides an alternative copper-secretion mechanism in Gram-negative bacteria (Lima et al. 2022).