An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis

Science. 2009 Oct 30;326(5953):722-6. doi: 10.1126/science.1176326. Epub 2009 Sep 17.


Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of genes responsible for iron uptake, release, use, and storage through the actions of the iron regulatory proteins IRP1 and IRP2. However, the manner in which iron levels are sensed to affect IRP2 activity is poorly understood. We found that an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation. The stability of FBXL5 itself was regulated, accumulating under iron- and oxygen-replete conditions and degraded upon iron depletion. FBXL5 contains an iron- and oxygen-binding hemerythrin domain that acted as a ligand-dependent regulatory switch mediating FBXL5's differential stability. These observations suggest a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation, and cellular responses to maintain mammalian iron homeostasis.

Publication types

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

MeSH terms

  • Catalytic Domain
  • Cell Line
  • F-Box Proteins / chemistry
  • F-Box Proteins / metabolism*
  • HeLa Cells
  • Hemerythrin / metabolism*
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Iron Regulatory Protein 2 / metabolism
  • Oxygen / metabolism
  • Protein Structure, Tertiary
  • RNA, Small Interfering
  • Recombinant Fusion Proteins / metabolism
  • Ubiquitin-Protein Ligase Complexes
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism*


  • F-Box Proteins
  • FBXL5 protein, human
  • Hemerythrin
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Iron
  • Ubiquitin-Protein Ligase Complexes
  • Ubiquitin-Protein Ligases
  • IREB2 protein, human
  • Iron Regulatory Protein 2
  • Oxygen