Posttranscriptional regulation of iron homeostasis by iron regulatory protein 2.
Iron-regulatory proteins (IRPs) are cytoplasmic proteins that bind to RNA stem-loop structures termed iron-responsive elements (IREs) present in either the 5'- or 3' untranslated regions (UTR) of mRNAs involved in iron metabolism. Binding of IRPs to IREs in 5' UTRs represses mRNA translation, whereas binding of IRPs to IREs in 3' UTRs stabilizes mRNA. Two IRPs known as IRP1 and IRP2 have been identified. The function and regulation of IRP1 have been extensively studied in the last five years. IRP1 is a dual function protein acting as a RNA binding protein when iron is scarce, and a cytoplasmic aconitase when iron is abundant. Little was known about the structural and biochemical characteristics of IRP2. In order to understand the role of IRP2 in cellular iron metabolism, IRP2 was purified from rat liver and the gene encoding it cloned from a rat cDNA library. Biochemical characterization showed that both IRP1 and IRP2 bind to different IREs with similar affinities and function as translational repressors during in vitro translation. IRP2, however, is different from IRP1 in the following aspects. First, unlike IRP1, IRP2 does not exhibit aconitase activity. Second, although IRP2 shares 61% amino acid identity with IRP1 and contains the three cysteines that coordinate the 4Fe-4S cluster in IRP1, it also contains a cysteine/proline rich 73 amino acid insert and has substitutions at two aconitase active site residues. Third, although iron reduces the IRE-binding activities of both IRP1 and IRP2, IRP1 protein levels remain constant, whereas IRP2 protein levels are reduced. The reduction in IRP2 protein levels is due to increased turnover of IRP2. The degradation of IRP2 requires protein synthesis and is mediated by the proteasome. These data not only showed that a new iron-regulatory protein is present and it is regulated differently from the already characterized IRP1 but also raised questions as to the role of IRP2 in iron homeostasis.
University of Utah;
University of Utah;
Relation-Is Version Of
Digital reproduction of “Posttranscriptional regulation of iron homeostasis by iron regulatory protein 2.” Spencer S. Eccles Health Sciences Library. Print version of “Posttranscriptional regulation of iron homeostasis by iron regulatory protein 2.” available at J. Willard Marriott Library Special Collection. QP6.5 1995 .G86.