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Article Dans Une Revue Biochemical Journal Année : 2007

Human iron regulatory protein 2 is easily cleaved in its specific domain: consequences for the heme binding properties of the protein

Résumé

Mammalian Iron Regulatory Proteins, IRP1 and IRP2, are cytosolic RNA-binding proteins that post-transcriptionally control the mRNA of proteins involved in storage, transport, and utilization of iron. In iron-replete cells, IRP2 undergoes degradation by the ubiquitin/proteasome pathway. Binding of heme to a 73 amino acids domain (73aa-Domain) that is unique in IRP2 has been previously proposed as the initial iron-sensing mechanism. It is shown here that recombinant IRP2 and the 73aa-Domain are sensitive to proteolysis at the same site. Nuclear Magnetic Resonance data suggest that the isolated 73aa-Domain is not structured. Iron-independent cleavage of IRP2 within the 73aa-Domain also occurs in lung cancer (H1299) cells. Heme interacts with a cysteine residue only in truncated forms of the 73aa-Domain, as shown by a series of complementary physico-chemical approaches, including Nuclear Magnetic Resonance, Electron Paramagnetic Resonance, and ultra-violet visible absorption spectroscopy. In contrast, the cofactor is not ligated by the same residue in the full-length peptide or intact IRP2, although non specific interaction occurs between these molecular forms and heme. Therefore it is unlikely that the iron-dependent degradation of IRP2 is mediated by heme binding to the intact 73aa-Domain, since the sequence resembling a Heme Regulatory Motif in the 73aa-Domain does not provide an axial ligand of the cofactor unless this domain is cleaved.

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Dates et versions

hal-00478851 , version 1 (30-04-2010)

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Camille Dycke, Catherine M Bougault, Jacques Gaillard, Jean-Pierre Andrieu, Kostas Pantopoulos, et al.. Human iron regulatory protein 2 is easily cleaved in its specific domain: consequences for the heme binding properties of the protein. Biochemical Journal, 2007, 408 (3), pp.429-439. ⟨10.1042/BJ20070983⟩. ⟨hal-00478851⟩
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