Mol. Cell 78, 31–41 (2020)

In mammalian cells, iron homeostasis is regulated through iron regulatory proteins binding to iron-responsive mRNA elements. As part of this process, F-box and leucine-rich repeat protein 5 (FBXL5) binds to and promotes the ubiquitin-mediated degradation of iron regulatory protein 2 (IRP2) when iron is plentiful. In the course of investigating how FBXL5 recognizes IRP2, Wang and Shi et al. uncovered an iron–sulfur cluster in FBXL5. Structure determination of the FBXL5–IRP2 complex by cryo-EM revealed that although the cluster is not directly at the FBXL5–IRP2 interface, it contributes to IRP2 recognition via a hydrogen bonding network involving the backbone of two of the cluster’s cysteine ligands. Blocking cluster binding through mutagenesis or chemical reduction of the cluster prevented IRP2 recruitment, indicating its role as a redox switch controlling oxygen dependence for IRP2 binding. The role of this iron–sulfur cluster in regulating FBXL5–IRP2 recognition illustrates one method by which the cell senses and responds to iron and oxygen availability.