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J. Biol. Chem., Vol. 279, Issue 44, 45450-45454, October 29, 2004

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Identification of a Heme-sensing Domain in Iron Regulatory Protein 2^*

Jinsook Jeong, Tracey A. Rouault, and Rodney L. Levine¶

From the Laboratory of Biochemistry, NHLBI, National Institutes of Health and the Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Iron regulatory protein 2 coordinates the cellular regulation of iron metabolism by binding to iron-responsive elements in mRNA. The protein is synthesized constitutively but is rapidly degraded when iron stores are replete. The mechanisms that prevent degradation during iron deficiency or promote degradation during iron sufficiency are not delineated. Iron regulatory protein 2 contains a domain not present in the closely related iron regulatory protein 1, and we found that this domain binds heme with high affinity. A cysteine within the domain is axially liganded to the heme, as occurs in cytochrome P450. The protein-bound heme reacts with molecular oxygen to mediate the oxidation of cysteine, including -elimination of the sulfur to yield alanine. This covalent modification may thus mark the protein molecule for degradation by the proteasome system, providing another mechanism by which heme can regulate the level of iron regulatory protein 2.

Received for publication, July 7, 2004 , and in revised form, August 6, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed, preferably via e-mail: National Institutes of Health, Bldg. 50, Rm. 2351, Bethesda, MD 20892-0812; Tel.: 301-496-2310; Fax: 301-496-0599; E-mail: rlevine{at}nih.gov.

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