Iron-Sulfur Protein Biogenesis and Function

Iron–sulfur proteins contain inorganic clusters of iron and sulfur that act as versatile cofactors in electron transfer, enzyme catalysis and regulatory sensing. Biogenesis of these clusters is a conserved multi-step process orchestrated by specialised protein machineries in mitochondria, the cytosol and bacteria. In mitochondria, a core assembly complex synthesises [2Fe-2S] and [4Fe-4S] clusters on a scaffold protein before transferring them to recipient apoproteins. A separate cytosolic iron–sulfur assembly (CIA) pathway supports nuclear and cytoplasmic enzymes involved in DNA replication, repair and metabolism, while bacteria deploy ISC and SUF systems tuned to environmental stress. Recent mechanistic studies have elucidated how persulfide intermediates are generated, how iron is delivered and how accessory factors regulate the speed and fidelity of cluster delivery. Disruptions in these pathways underlie human disorders such as Friedreich’s ataxia and sideroblastic anaemia, and influence microbial survival and pathogenicity. A detailed understanding of iron–sulfur protein biogenesis promises advances in therapies for mitochondrial disease, novel antimicrobial strategies and optimisation of industrial biocatalysts.

Research from Nature Portfolio

Recent structural and biochemical analyses have captured high-resolution snapshots of sulphur transfer during de novo [2Fe-2S] cluster assembly on the mitochondrial scaffold. Anaerobic cryo-EM studies reveal successive persulfide hand-off from the cysteine desulfurase to key cysteine residues on the scaffold protein, and define how the iron-chaperone positions active-site residues for rapid cluster formation. In parallel, cryo-EM structures of the human core assembly complex bound to its activating factor demonstrate how frataxin reshapes loop conformations and modulates a regulatory zinc site that would otherwise inhibit the desulfurase. Together, these findings clarify the molecular choreography of iron insertion, sulphur mobilisation and cluster maturation within the mitochondrial framework.

Iron-Sulfur Protein Biogenesis and Function publication trend

The graph below shows the total number of articles in iron-sulfur protein biogenesis and function across all publications each year (not limited to Nature Index journals).

Technical terms

Iron–sulfur cluster: Inorganic cofactor comprising iron and sulphide atoms, commonly in [2Fe-2S] or [4Fe-4S] arrangements, that mediates electron transfer and catalytic functions.

Cysteine desulfurase: Enzyme that converts cysteine to alanine, forming a persulfide intermediate that supplies sulfur for cluster assembly.

Scaffold protein: Transient assembly platform on which nascent iron–sulfur clusters are synthesised before transfer to recipient proteins.

Persulfide: Sulfur-containing intermediate with an –SSH moiety, crucial for controlled sulphur delivery during cluster assembly.

Frataxin: Iron-binding accessory factor that enhances persulfide transfer and regulates desulfurase activity within the assembly complex.

Cytosolic iron–sulfur assembly (CIA) machinery: Network of proteins dedicated to cluster insertion into nuclear and cytosolic apoproteins, supporting genome maintenance and metabolic pathways.

References

1. Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2. Nature Communications (2024).
2. Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism. Nature Communications (2019).
3. CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes. Journal of Clinical Investigation (2024).
4. The Fe-S cluster biosynthesis in Enterococcus faecium is essential for anaerobic growth and gastrointestinal colonization. Gut Microbes (2024).
5. Iron–sulfur cluster biogenesis and trafficking in mitochondria. Journal of Biological Chemistry (2017).