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J. Biol. Chem., Vol. 277, Issue 14, 11995-12000, April 5, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/14/11995    most recent M110938200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brazzolotto, X. Articles by Moulis, J.-M. Search for Related Content PubMed PubMed Citation Articles by Brazzolotto, X. Articles by Moulis, J.-M. Social Bookmarking                      What's this?

Structural Changes Associated with Switching Activities of Human Iron Regulatory Protein 1^*

Xavier Brazzolotto, Peter Timmins^§, Yves Dupont^¶, and Jean-Marc Moulis

From the  Commissariat à l'Energie Atomique-Grenoble, Département de Biologie Moléculaire et Structurale, 38054 Grenoble Cedex 9, France, ^§ Large Scale Structures Group, Institut Laue-Langevin, 6 rue Jules Horowitz, BP156, 38042 Grenoble Cedex 9, France, and ^¶ Commissariat à l'Energie Atomique-Grenoble, Département de Biologie Moléculaire et Structurale, Laboratoire BMC, 38054 Grenoble Cedex 9, France

Metazoan iron regulatory protein 1 is a dual activity protein, being either an aconitase or a regulatory factor binding to messenger RNA involved in iron homeostasis. Sequence comparisons and site-directed mutagenesis experiments have supported a structural relationship between mitochondrial aconitase and iron regulatory protein 1. The structural properties of human recombinant iron regulatory protein 1 have been probed in the present work. Although iron-free iron regulatory protein 1 displays a significantly larger radius of gyration measured by small-angle neutron scattering than calculated for mitochondrial aconitase, binding of either the [4Fe-4S] cluster needed for aconitase activity or of a RNA substrate turns iron regulatory protein 1 into a more compact molecule. These conformational changes are associated with the gain of secondary structural elements as indicated by circular dichroism studies. They likely involve -helices covering the substrate binding cleft of cytosolic aconitase, and they suggest an induced fit mechanism of iron-responsive element recognition. These studies refine previously proposed models of the "iron-sulfur switch" driving the biological function of human iron regulatory protein 1, and they provide a structural framework to probe the relevance of the numerous cellular molecules proposed to affect its function.

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