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  • Review Article
  • Published:

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

Nature Reviews Microbiology volume 7, pages 25–35 (2009)Cite this article

An Erratum to this article was published on 31 December 2008

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, P1-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 transcriptional regulators (Fur, DtxR, NikR, MerR, ArsR–SmtB, CsoR–RcnR and CopY). The metal affinities of these proteins can determine the boundaries between metal sufficiency and metal excess or deficiency for each element. These affinities become increasingly tight on moving up the Irving–Williams series, such that the metals at the top of the series must be bound and buffered to extremely low concentrations.

  • Some metals are passed to the correct metalloproteins by dedicated delivery pathways that involve metallochaperones, in which case the specificity of a protein–protein interaction can ensure that only the correct proteins acquire the metal.

  • Metal discrimination by the proteins of metal homeostasis is especially important if these proteins influence metal occupancy of other metalloproteins. Analysis of nickel specificity by the DNA-binding repressor NmtR from Mycobacterium tuberculosis revealed that the discernment of metals by metal sensors can be determined by the sensors' allosteric mechanism and/or its access to metal, which is predicted to be a function of the relative metal affinities of the cells complement of metal sensors.

Abstract

Protein metal-coordination sites are richly varied and exquisitely attuned to their inorganic partners, yet many metalloproteins still select the wrong metals when presented with mixtures of elements. Cells have evolved elaborate mechanisms to scavenge for sufficient metal atoms to meet their needs and to adjust their needs to match supply. Metal sensors, transporters and stores have often been discovered as metal-resistance determinants, but it is emerging that they perform a broader role in microbial physiology: they allow cells to overcome inadequate protein metal affinities to populate large numbers of metalloproteins with the right metals.

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Figure 1: Localization-dependent ligand binding and trapping through folding.
Figure 2: The complement of metal transporters in Escherichia coli.
Figure 3: The complement of metal sensors in Escherichia coli.
Figure 4: Pathways of metal supply.

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Acknowledgements

The authors have been supported by Biotechnology and Biological Sciences Research Council (BBSRC) Plant and Microbial Sciences (PMS) grant BB/E001688/1.

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  1. Institute for Cell and Molecular Biosciences, Medical School, University of Newcastle, NE2 4HH, UK

    Kevin J. Waldron & Nigel J. Robinson

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  1. Kevin J. Waldron
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Correspondence to Nigel J. Robinson.

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DDATABASES

Entrez Genome Project

Bacillus subtilis

Corynebacterium diphtheriae

Escherichia coli

Helicobacter pylori

Mycobacterium tuberculosis

Staphylococcus aureus

Synechocystis sp. PCC 6803

FURTHER INFORMATION

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Glossary

Lewis acid

A chemical that can accept a pair of electrons from a Lewis base.

Thiophilic

A strong binder to thiol sulphurs.

Porin

A β-barrel protein that allows the diffusion of molecules (up to ∼1.5 kDa) across the outer membrane.

Antiport

Coupled transport of two molecules in opposing directions.

Metallothionein

A small, cysteine-rich metal-binding protein.

Apoprotein

A protein without a metal cofactor.

Holoprotein

A mature protein with a metal cofactor.

Winged helix–turn–helix structure

A structure found in many DNA-binding proteins with wings formed by a pair of β-strands.

d–d transition

An electronic transition between d-orbitals in a metal atom.

Tetrahedral geometry

Four atoms are arranged around a central atom, thereby defining the vertices of a tetrahedron.

Octahedral geometry

Six atoms are symmetrically arranged around a central atom, thereby defining the vertices of an octahedron.

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Waldron, K., Robinson, N. How do bacterial cells ensure that metalloproteins get the correct metal?. Nat Rev Microbiol 7, 25–35 (2009). https://doi.org/10.1038/nrmicro2057

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