How do bacterial cells ensure that metalloproteins get the correct metal?

Key Points More than 25% of proteins are thought to need metals, such as zinc, iron, copper, cobalt, nickel, manganese, magnesium and calcium. Proteins tend to bind metals such as copper and zinc tightly, but bind metals such as manganese, magnesium and calcium weakly, and for essential divalent cations the order of affinity is defined by the Irving–Williams stability series. Some non-essential metals, such as cadmium and mercury, can also be highly competitive. The cell must supply sufficient atoms of each metal to satisfy the demands of proteins that require the element and must also act to keep the tight-binding metals out of the binding sites of proteins that require weaker-binding metals. Mechanisms by which cells meet this challenge to correctly populate metalloproteins have been proposed, although to date few studies have explicitly set out to test them. By restricting the numbers of metal atoms within the cytoplasm, it is presumed that rather than metals competing with other metals for a limited pool of protein, each protein competes with other proteins for a limited pool of metal. Under these conditions, metal occupancy is determined by the relative metal affinities of the different proteins rather than their absolute affinities. However, this requires precise control over the numbers of atoms of each metal and molecules of the respective metalloproteins. A balance between the actions of importers and exporters for each metal controls how many atoms accumulate in the cell. The catalogue of metal transporters includes ATP-binding cassette-type ATPases, P 1 -type ATPases, RND (resistance and nodulation), CDF (cation diffusion facilitator) and NiCoT (Ni and Co transporter) proteins, CorA (Co resistance), NRAMP (natural resistance associated with macrophage protein) and ZIP (Zrt/Irt-like protein)-family transporters. The number of protein binding sites for each metal can be adjusted to match metal supply; for example, by switching from a protein that requires iron to one that uses copper when it becomes available or iron becomes limiting. The synthesis of storage proteins, such as metallothioneins for zinc or ferritins for ferric iron, sequesters surplus metal atoms to restrain them from other binding sites. Expression of genes that encode metal transporters and storage proteins is generally controlled by metal sensors, including two-component histidine kinases and response regulators plus seven known families of soluble DNA-binding, metal-binding tra