Zinc and cadmium specifically interfere with RNA-binding activity of human iron regulatory protein 1.
The cellular pro-oxidative stress induced by high zinc concentrations or cadmium is most likely mediated by disruption of redox (mainly thiol) homeostasis or by mishandling of redox-active transition metals. The impact of zinc and cadmium on the main regulators of iron homeostasis in metazoans, the iron regulatory proteins (IRP) 1 and 2, has been probed with the human recombinant proteins. Using purified proteins or extracts of yeast producing human IRP, zinc and cadmium were shown to interfere with the IRE-binding activity of IRP1, but not with that of IRP2 or the aconitase activity of IRP1. The IRP1 active site cysteines in positions 437, 503 and 506 were not directly involved in the effects of zinc and cadmium. The loss of RNA-binding activity is due to the reversible and specific aggregation of the IRP1 apoprotein with zinc and cadmium, since precipitation did not occur with other divalent metals such as manganese, cobalt or magnesium. The reported data suggest a new mechanism for the biological toxicity of cadmium and high zinc concentrations by interference with iron metabolism.
Département Réponse et Dynamique Cellulaires, Laboratoire de Biophysique Moléculaire et Cellulaire - UMR-CNRS 5090-Université Joseph-Fourier, Commissariat à l'Energie Atomique de Grenoble, 17 avenue des Martyrs, 38054 Grenoble cedex 9, France.
Alain
A
Martelli
Jean-Marc
JM
Moulis
D002104:Cadmium / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015032:Zinc / Q000378:metabolism*
D020033:Protein Isoforms; D011994:Recombinant Proteins; D002104:Cadmium; D012313:RNA; D007501:Iron; D035941:Iron Regulatory Protein 1; D015032:Zinc