Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 314 (5807): 1903-1908

Copyright © 2006 by the American Association for the Advancement of Science

Structure of Dual Function Iron Regulatory Protein 1 Complexed with Ferritin IRE-RNA

William E. Walden,1 Anna I. Selezneva,1 Jérôme Dupuy,2 Anne Volbeda,2 Juan C. Fontecilla-Camps,2 Elizabeth C. Theil,3 Karl Volz1*

Abstract: Iron regulatory protein 1 (IRP1) binds iron-responsive elements (IREs) in messenger RNAs (mRNAs), to repress translation or degradation, or binds an iron-sulfur cluster, to become a cytosolic aconitase enzyme. The 2.8 angstrom resolution crystal structure of the IRP1:ferritin H IRE complex shows an open protein conformation compared with that of cytosolic aconitase. The extended, L-shaped IRP1 molecule embraces the IRE stem-loop through interactions at two sites separated by ~30 angstroms, each involving about a dozen protein:RNA bonds. Extensive conformational changes related to binding the IRE or an iron-sulfur cluster explain the alternate functions of IRP1 as an mRNA regulator or enzyme.

1 Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612–7344, USA.
2 Laboratoire de Cristallographie et de Cristallogénèse des Protéins, IBS, Institut de Biologie Structurale Jean-Pierre Ebel; CEA; CNRS; Université Joseph Fourier, 41 rue Jules Horowitz, F-38207 Grenoble, France.
3 Children's Hospital Oakland Research Institute, Oakland, CA 94609–1673, and Department of Nutritional Science and Molecular Toxicology, University of California, Berkeley, Berkeley, CA 94720–3104, USA.

* To whom correspondence should be addressed. E-mail: kvolz{at}uic.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
X-ray snapshots of possible intermediates in the time course of synthesis and degradation of protein-bound Fe4S4 clusters.
Y. Nicolet, R. Rohac, L. Martin, and J. C. Fontecilla-Camps (2013)
PNAS 110, 7188-7192
   Abstract »    Full Text »    PDF »
Two Roles for Aconitase in the Regulation of Tricarboxylic Acid Branch Gene Expression in Bacillus subtilis.
K. B. Pechter, F. M. Meyer, A. W. Serio, J. Stulke, and A. L. Sonenshein (2013)
J. Bacteriol. 195, 1525-1537
   Abstract »    Full Text »    PDF »
Neurodegenerative diseases: Quantitative predictions of protein-RNA interactions.
D. Cirillo, F. Agostini, P. Klus, D. Marchese, S. Rodriguez, B. Bolognesi, and G. G. Tartaglia (2013)
RNA 19, 129-140
   Abstract »    Full Text »    PDF »
Fe2+ binds iron responsive element-RNA, selectively changing protein-binding affinities and regulating mRNA repression and activation.
J. Ma, S. Haldar, M. A. Khan, S. D. Sharma, W. C. Merrick, E. C. Theil, and D. J. Goss (2012)
PNAS 109, 8417-8422
   Abstract »    Full Text »    PDF »
Deletion of the Aconitase Gene in Corynebacterium glutamicum Causes Strong Selection Pressure for Secondary Mutations Inactivating Citrate Synthase.
M. Baumgart, N. Mustafi, A. Krug, and M. Bott (2011)
J. Bacteriol. 193, 6864-6873
   Abstract »    Full Text »    PDF »
Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins.
M. Sanchez, B. Galy, B. Schwanhaeusser, J. Blake, T. Bahr-Ivacevic, V. Benes, M. Selbach, M. U. Muckenthaler, and M. W. Hentze (2011)
Blood 118, e168-e179
   Abstract »    Full Text »    PDF »
Iron Homeostasis and Nutritional Iron Deficiency.
E. C. Theil (2011)
J. Nutr. 141, 724S-728S
   Abstract »    Full Text »    PDF »
Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1.
H.-H. Cho, C. M. Cahill, C. R. Vanderburg, C. R. Scherzer, B. Wang, X. Huang, and J. T. Rogers (2010)
J. Biol. Chem. 285, 31217-31232
   Abstract »    Full Text »    PDF »
Cytosolic Iron-Sulfur Cluster Assembly (CIA) System: Factors, Mechanism, and Relevance to Cellular Iron Regulation.
A. K. Sharma, L. J. Pallesen, R. J. Spang, and W. E. Walden (2010)
J. Biol. Chem. 285, 26745-26751
   Abstract »    Full Text »    PDF »
Reversal of Age-associated Oxidative Stress in Rats by MRN-100, a Hydro-ferrate Fluid.
N. K. BADR EL-DIN, E. NOAMAN, S. M. A. FATTAH, and M. GHONEUM (2010)
In Vivo 24, 525-533
   Abstract »    Full Text »    PDF »
Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy.
J. B. Goforth, S. A. Anderson, C. P. Nizzi, and R. S. Eisenstein (2010)
RNA 16, 154-169
   Abstract »    Full Text »    PDF »
Mining ferritin iron: 2 pathways.
E. C. Theil (2009)
Blood 114, 4325-4326
   Full Text »    PDF »
An Ancient Gauge for Iron.
T. A. Rouault (2009)
Science 326, 676-677
   Abstract »    Full Text »    PDF »
Direct Fe2+ Sensing by Iron-responsive Messenger RNA{middle dot}Repressor Complexes Weakens Binding.
M. A. Khan, W. E. Walden, D. J. Goss, and E. C. Theil (2009)
J. Biol. Chem. 284, 30122-30128
   Abstract »    Full Text »    PDF »
Cysteine Oxidation Regulates the RNA-Binding Activity of Iron Regulatory Protein 2.
K. B. Zumbrennen, M. L. Wallander, S. J. Romney, and E. A. Leibold (2009)
Mol. Cell. Biol. 29, 2219-2229
   Abstract »    Full Text »    PDF »
Protein Dynamism and Evolvability.
N. Tokuriki and D. S. Tawfik (2009)
Science 324, 203-207
   Abstract »    Full Text »    PDF »
Knockdown of proteins involved in iron metabolism limits tick reproduction and development.
O. Hajdusek, D. Sojka, P. Kopacek, V. Buresova, Z. Franta, I. Sauman, J. Winzerling, and L. Grubhoffer (2009)
PNAS 106, 1033-1038
   Abstract »    Full Text »    PDF »
Interaction of anthracyclines with iron responsive element mRNAs.
J. C. Canzoneri and A. K. Oyelere (2008)
Nucleic Acids Res. 36, 6825-6834
   Abstract »    Full Text »    PDF »
An Iron Responsive Element-like Stem-Loop Regulates {alpha}-Hemoglobin-stabilizing Protein mRNA.
C. O. dos Santos, L. C. Dore, E. Valentine, S. G. Shelat, R. C. Hardison, M. Ghosh, W. Wang, R. S. Eisenstein, F. F. Costa, and M. J. Weiss (2008)
J. Biol. Chem. 283, 26956-26964
   Abstract »    Full Text »    PDF »
Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice.
M. C. Ghosh, W.-H. Tong, D. Zhang, H. Ollivierre-Wilson, A. Singh, M. C. Krishna, J. B. Mitchell, and T. A. Rouault (2008)
PNAS 105, 12028-12033
   Abstract »    Full Text »    PDF »
Forging a field: the golden age of iron biology.
N. C. Andrews (2008)
Blood 112, 219-230
   Full Text »    PDF »
DNA mimicry by a high-affinity anti-NF-{kappa}B RNA aptamer.
N. J. Reiter, L. J. Maher III, and S. E. Butcher (2008)
Nucleic Acids Res. 36, 1227-1236
   Abstract »    Full Text »    PDF »
Zinc Deficiency-induced Iron Accumulation, a Consequence of Alterations in Iron Regulatory Protein-binding Activity, Iron Transporters, and Iron Storage Proteins.
B. J. Niles, M. S. Clegg, L. A. Hanna, S. S. Chou, T. Y. Momma, H. Hong, and C. L. Keen (2008)
J. Biol. Chem. 283, 5168-5177
   Abstract »    Full Text »    PDF »
Ferritin L and H Subunits Are Differentially Regulated on a Post-transcriptional Level.
M. C. Sammarco, S. Ditch, A. Banerjee, and E. Grabczyk (2008)
J. Biol. Chem. 283, 4578-4587
   Abstract »    Full Text »    PDF »
Bach1 Repression of Ferritin and Thioredoxin Reductase1 Is Heme-sensitive in Cells and in Vitro and Coordinates Expression with Heme Oxygenase1, beta-Globin, and NADP(H) Quinone (Oxido) Reductase1.
K. J. Hintze, Y. Katoh, K. Igarashi, and E. C. Theil (2007)
J. Biol. Chem. 282, 34365-34371
   Abstract »    Full Text »    PDF »
RsmA Is an Anti-sigma Factor That Modulates Its Activity through a [2Fe-2S] Cluster Cofactor.
A. A. Gaskell, J. C. Crack, G. H. Kelemen, M. I. Hutchings, and N. E. Le Brun (2007)
J. Biol. Chem. 282, 31812-31820
   Abstract »    Full Text »    PDF »
Yeast aconitase binds and provides metabolically coupled protection to mitochondrial DNA.
X. J. Chen, X. Wang, and R. A. Butow (2007)
PNAS 104, 13738-13743
   Abstract »    Full Text »    PDF »
Evolution of the iron-responsive element.
P. Piccinelli and T. Samuelsson (2007)
RNA 13, 952-966
   Abstract »    Full Text »    PDF »
BIOCHEMISTRY: If the RNA Fits, Use It.
T. A. Rouault (2006)
Science 314, 1886-1887
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882