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

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.

Pubmed ID: 19762597

Authors

  • Salahudeen AA
  • Thompson JW
  • Ruiz JC
  • Ma HW
  • Kinch LN
  • Li Q
  • Grishin NV
  • Bruick RK

Journal

Science (New York, N.Y.)

Publication Data

October 30, 2009

Associated Grants

  • Agency: NCRR NIH HHS, Id: C06 RR 15437-01
  • Agency: NCI NIH HHS, Id: CA115962
  • Agency: NCI NIH HHS, Id: R01 CA115962
  • Agency: NCI NIH HHS, Id: R01 CA115962-05

Mesh Terms

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