FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster

Mol Cell. 2020 Apr 2;78(1):31-41.e5. doi: 10.1016/j.molcel.2020.02.011. Epub 2020 Mar 2.


Cellular iron homeostasis is dominated by FBXL5-mediated degradation of iron regulatory protein 2 (IRP2), which is dependent on both iron and oxygen. However, how the physical interaction between FBXL5 and IRP2 is regulated remains elusive. Here, we show that the C-terminal substrate-binding domain of FBXL5 harbors a [2Fe2S] cluster in the oxidized state. A cryoelectron microscopy (cryo-EM) structure of the IRP2-FBXL5-SKP1 complex reveals that the cluster organizes the FBXL5 C-terminal loop responsible for recruiting IRP2. Interestingly, IRP2 binding to FBXL5 hinges on the oxidized state of the [2Fe2S] cluster maintained by ambient oxygen, which could explain hypoxia-induced IRP2 stabilization. Steric incompatibility also allows FBXL5 to physically dislodge IRP2 from iron-responsive element RNA to facilitate its turnover. Taken together, our studies have identified an iron-sulfur cluster within FBXL5, which promotes IRP2 polyubiquitination and degradation in response to both iron and oxygen concentrations.

Keywords: FBXL5; IRP2; cryo-EM; iron homeostasis; iron-sulfur cluster; oxygen-responsive.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line
  • F-Box Proteins / chemistry*
  • F-Box Proteins / metabolism
  • Homeostasis
  • Humans
  • Iron / metabolism
  • Iron Regulatory Protein 2 / chemistry*
  • Iron Regulatory Protein 2 / metabolism
  • Iron-Sulfur Proteins / chemistry
  • Iron-Sulfur Proteins / metabolism
  • Models, Molecular
  • Oxygen / chemistry*
  • Protein Binding
  • Protein Stability
  • S-Phase Kinase-Associated Proteins / chemistry
  • Ubiquitin-Protein Ligase Complexes / chemistry*
  • Ubiquitin-Protein Ligase Complexes / metabolism


  • F-Box Proteins
  • FBXL5 protein, human
  • Iron-Sulfur Proteins
  • S-Phase Kinase-Associated Proteins
  • SKP1 protein, human
  • Iron
  • Ubiquitin-Protein Ligase Complexes
  • IREB2 protein, human
  • Iron Regulatory Protein 2
  • Oxygen