Figure 6. Under physiological conditions, IRP1 is regulated by a reversible ISC switch.

Iron deficiency promotes ISC disassembly and a conformational rearrangement, resulting in the conversion of IRP1 from c-aconitase to an IRE-binding protein. The ISC is regenerated in iron-replete cells. Hypoxia favours maintenance of the ISC, whereas H₂O₂ or NO promote its disassembly. When the ISC-biogenesis pathway is not operational, iron leads to ubiquitination of apo-IRP1 by the FBXL5 E3 ligase complex (including Skp1, Cul1 and Rbx1), resulting in proteasomal degradation.