Studying the structure and function of a novel family of bacterial copper storage proteins

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Copper is an essential metal ion for most organisms, acting as a cofactor for key enzymes. However, copper can also have toxic effects on cells, and mechanisms have evolved for its safe handling. We have discovered a new family of proteins that allow bacteria to safely store copper (Nature 2015, 525, 140-143). These proteins (the Csps) were identified in methane-oxidising bacteria (methanotrophs), where they store copper for the main enzyme that oxidises methane, a potent greenhouse gas. Csp homologues are widespread in methanotrophs and a range of other bacteria, including important pathogens. As copper is thought to be used by hosts to attack invading pathogens, the presence of a protein that can defend by soaking up large quantities of copper ions could be key for virulence. A better understanding of the role of Csps in copper handling by bacteria is clearly required, which will be achieve using a range of in vitro and in vivo approaches. This work can be carried out in methanotrophs, pathogens, or the widely used model organism Bacillus subtilis. Methanotrophs, such as Methylosinus trichosporium OB3b in which the Csps were originally discovered, can possess a cytosolic Csp3 and an exported Csp1. The latter has been shown to store Cu(I) for the almost ubiquitous membrane-bound particulate methane monooxygenase (pMMO). Both of these Csps from M. trichosporium OB3b have been characterised in vitro (Nature 2015, 525, 140-143; Sci. Rep. 2016, 6:39065) and display striking differences in terms of how Cu(I) binds (Angew. Chem. Int. Ed. Engl. 2017, 56, 8697-8700) and the rate of Cu(I) removal. Understanding the structural features that are responsible for these differences and their influence on copper storage and removal within the methanotroph will be studied.Pathogens such as Neisseria gonorrhoeae, Salmonella enterica sv. Typhimurium, Pseudomonas aeruginosa, and the Burkholderia cepacia complex can possess either a Csp1 or Csp3. Analysing the in vitro properties of these Csps and their potential role in pathogenicity is another area in which studies can be undertaken. An appealing possibility is to compare Csp3s from P. aeruginosa strains and Csp1s from the B. cepacia complex. Both of these opportunistic pathogens can develop multi-drug resistance and are a major concern for patients with cystic fibrosis. Understanding the role of the Csps in these organisms and their potential influence on pathogenesis could help in developing new antimicrobials.