Sustainable fisheries

metals such as copper. Once the manganese protein has folded, the metal-binding sites are inaccessible to other metals, and the protein can be safely exposed to the periplasmic envi­ ronment. In other words, the metal that binds to the protein is selected by the compartment in which the protein folds. Tottey and colleagues suggest that cytoplas­ mic metal insertion might be crucial not only for periplasmic proteins that bind individual metal ions, but also for the numerous Tat substrates that bind to other kinds of metalcontaining cofactors, such as clusters of metal and sulphur atoms or complexes of metals with organic molecules. They propose that cytoplas­ mic insertion prevents the misincorporation of tightly binding metals into such cofactors; once ensconced within the folded protein, the cofac­ tors are shielded from any interference by com­ peting metals. For example, the authors note that iron–sulphur clusters are susceptible to the misincorporation of transition-metal ions such as cobalt and copper, and that periplasmic proteins that contain iron–sulphur clusters are always transported to their site of action by the Tat pathway. Strikingly, and consistent with the authors’ proposal, the only periplasmic protein that has a copper–sulphur cofactor receives this cluster in the periplasm, rather than in the cytoplasm. Eukaryotic cells (such as those of animals, plants and fungi) might also control the metal loading of their secreted proteins by a varia­ tion of the protected-compartment strategy. In these cells, secreted proteins fold in the endo­ plasmic reticulum — an intracellular organelle that controls the concentrations of metal ions in its interior — before they reach the extra­ cellular milieu. But in contrast to the mecha­ nism described by Tottey et al., these folded 3. Irving, H. & Williams, R. J. P. Nature 162, 746–747 (1948). 4. Fraústo da Silva, J. J. R. & Williams, R. J. P. The Biological Chemistry of the Elements 2nd edn (Oxford Univ. Press, 2001). 5. Berks, B. C., Palmer, T. & Sargent, F. Adv. Microb. Physiol. 47, 187–254 (2003). 6. Ranquet, C., Ollagnier-de-Choudens, S., Loiseau, L., Barras, F. & Fontecave, M. J. Biol. Chem. 282, 30442–30451 (2007). 7. Butt, J. N., Niles, J., Armstrong, F. A., Breton, J. & Thomson, A. J. Nature Struct. Biol. 1, 427–433 (1994). 8. Zumft, W. G. & Kroneck, P. M. Adv. Microb. Physiol. 52, 107–227 (2007).