This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zumbrennen, K. B.
Right arrow Articles by Leibold, E. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zumbrennen, K. B.
Right arrow Articles by Leibold, E. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2009, p. 2219-2229, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.00004-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cysteine Oxidation Regulates the RNA-Binding Activity of Iron Regulatory Protein 2{triangledown} ,{dagger}

Kimberly B. Zumbrennen,1 Michelle L. Wallander,1,{ddagger} S. Joshua Romney,2 and Elizabeth A. Leibold1,2*

Department of Oncological Sciences,1 Department of Medicine, University of Utah, Salt Lake City, Utah2

Received 2 January 2009/ Accepted 30 January 2009

Iron regulatory protein 2 (IRP2) is an RNA-binding protein that regulates the posttranscriptional expression of proteins required for iron homeostasis such as ferritin and transferrin receptor 1. IRP2 RNA-binding activity is primarily regulated by iron-mediated proteasomal degradation, but studies have suggested that IRP2 RNA binding is also regulated by thiol oxidation. We generated a model of IRP2 bound to RNA and found that two cysteines (C512 and C516) are predicted to lie in the RNA-binding cleft. Site-directed mutagenesis and thiol modification show that, while IRP2 C512 and C516 do not directly interact with RNA, both cysteines are located within the RNA-binding cleft and must be unmodified/reduced for IRP2-RNA interactions. Oxidative stress induced by cellular glucose deprivation reduces the RNA-binding activity of IRP2 but not IRP2-C512S or IRP2-C516S, consistent with the formation of a disulfide bond between IRP2 C512 and C516 during oxidative stress. Decreased IRP2 RNA binding is correlated with reduced transferrin receptor 1 mRNA abundance. These studies provide insight into the structural basis for IRP2-RNA interactions and reveal an iron-independent mechanism for regulating iron homeostasis through the redox regulation of IRP2 cysteines.

* Corresponding author. Mailing address: Eccles Institute of Human Genetics, University of Utah, 15 North 2030 East, Room 3240A, Salt Lake City, UT 84112. Phone: (801) 585-5002. Fax: (801) 585-3501. E-mail: betty.leibold{at}genetics.utah.edu

{triangledown} Published ahead of print on 17 February 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT.

Molecular and Cellular Biology, April 2009, p. 2219-2229, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.00004-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Petroutsos, D., Terauchi, A. M., Busch, A., Hirschmann, I., Merchant, S. S., Finazzi, G., Hippler, M. (2009). PGRL1 Participates in Iron-induced Remodeling of the Photosynthetic Apparatus and in Energy Metabolism in Chlamydomonas reinhardtii. J. Biol. Chem. 284: 32770-32781 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»