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Mammalian iron–sulphur proteins: novel insights into biogenesis and function

Nature Reviews Molecular Cell Biology volume 16, pages 45–55 (2015)Cite this article

Subjects

Key Points

  • Iron–sulphur (Fe–S) clusters are flexible cofactors composed of iron and inorganic sulphur that are often ligated to proteins through cysteinyl ligands.

  • Unusual chemical features of the Fe–S cluster enable it to facilitate reduction–oxidation reactions and to carry out numerous complex chemical reactions and sensing activities.

  • Fe–S proteins are known to be pervasive in bacteria, and recent evidence suggests that they are also common in mammalian cells, in which they have often been missed because of their inherent instability and non-coloured appearance.

  • Fe–S clusters are synthesized by a complex series of reactions involving numerous proteins.

  • Many Fe–S cluster recipient proteins contain a Leu-Tyr-Arg motif to which a co-chaperone of the assembly apparatus binds, facilitating transfer of nascent clusters from a scaffold carrier to a final recipient protein.

  • De novo synthesis of Fe–S clusters does not require a mitochondrial precursor in bacteria and may not depend on export of a mitochondrial molecule in mammalian cytosolic and nuclear proteins.

  • Ten human diseases are now attributed to defective Fe–S cluster assembly, but differences in the severity and affected tissues of these diseases are not yet well explained.

Abstract

Iron–sulphur (Fe–S) clusters are inorganic cofactors that are found in nearly all species and are composed of various combinations of iron and sulphur atoms. Fe–S clusters can accept or donate single electrons to carry out oxidation and reduction reactions and to facilitate electron transport. Many details of how these complex modular structures are assembled and ligated to cellular proteins in the mitochondrial, nuclear and cytosolic compartments of mammalian cells remain unclear. Recent evidence indicates that a Leu-Tyr-Arg (LYR) tripeptide motif found in some Fe–S recipient proteins may facilitate the direct and shielded transfer of Fe–S clusters from a scaffold to client proteins. Fe–S clusters are probably an unrecognized and elusive cofactor of many known proteins.

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Figure 1: Examples of various Fe–S clusters.
Figure 2: Initial Fe–S cluster assembly in bacteria.
Figure 3: The initial Fe–S cluster assembly complex in eukaryotic cells.
Figure 4: A model to explain how Fe–S clusters can be correctly positioned deep within proteins.

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Acknowledgements

This work was supported by the intramural programme of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA. The author thanks members of the Rouault group, particularly N. Maio, G. Holmes-Hampton and W. Hang-Tong for their help with the figures and narrative.

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  1. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Tracey A. Rouault

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Correspondence to Tracey A. Rouault.

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Glossary

Cofactors

Non-protein chemical compounds that are required for the biological activity of some proteins.

d orbitals

There are five atomic d orbitals, each of which can accommodate two electrons. In the case of transition metals, d orbitals are incompletely filled, allowing them to accept or donate single electrons (reduction or oxidation, respectively). Iron typically contains five electrons (ferric iron) or six electrons (ferrous iron) in its d orbitals.

Electron paramagnetic resonance

(EPR). A technique used to study chemical species with unpaired electrons. EPR spectroscopy has an important role in the understanding of organic and inorganic radicals, transition metal complexes and some biomolecules.

Mössbauer spectroscopy

A technique that uses a source that emits γ-rays to excite a sample to examine its oxidation state and bound ligands.

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Rouault, T. Mammalian iron–sulphur proteins: novel insights into biogenesis and function. Nat Rev Mol Cell Biol 16, 45–55 (2015). https://doi.org/10.1038/nrm3909

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