RNA-binding protein that binds to iron-responsive elements (IRES), which are stem-loop structures found in the 5'-UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3'-UTR of transferrin receptor mRNA. Binding to the IRE element in ferritin results in the repression of its mRNA translation. Binding of the protein to the transferrin receptor mRNA inhibits the degradation of this otherwise rapidly degraded mRNA. (updated: Oct. 10, 2018)
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
No sequence conservation computed yet.
Total structural coverage: 0%
No model available.
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The reference OMIM entry for this protein is 147582
Iron-responsive element-binding protein 2; ireb2
Ire-binding protein 2; irp2
CLONING
Rouault et al. (1990) identified a second IRE-binding protein, for which the degenerate screening of the oligonucleotide used in identifying the cDNA for IREB1 (
100880) also served as a successful sequencing primer. The second IREBP, represented by 'clone 10.1,' contained an inserted stretch of 73 amino acids between amino acids 37 and 38 of IREB1; the IREB2 gene product lacked a region homologous to the sequences between amino acids 436 and 470 of IREB1.
GENE FUNCTION
Hentze and Kuhn (1996) reviewed the function of IRP2. IRP2 is less abundant than IRP1 (IREB1) in most cells. The strongest expression is in intestine and brain (Henderson et al., 1993). Human IRP2 is 57% identical to human IRP1. IRP2 has a molecular mass of 105 kD, which is slightly larger than that of IRP1 due to a 73-amino acid insertion. Iwai et al. (1995) demonstrated that the 73-amino acid insertion mediates IRP2 degradation in iron-replete cells. Guo et al. (1994) and Samaniego et al. (1994) showed that IRP2 has no aconitase activity. Wu et al. (1999) demonstrated that the c-myc (
190080) protein stimulates expression of IRP2. Meyron-Holtz et al. (2004) found that IRP2-null cells misregulated iron metabolism when cultured in 3 to 6% oxygen, which is comparable to physiologic tissue concentrations, but not in 21% oxygen, a concentration that activated IRP1 (
100880) and allowed it to substitute for IRP2. Thus, IRP2 dominates regulation of mammalian iron homeostasis because it alone registers iron concentrations and modulates its RNA-binding activity at physiologic oxygen tensions. Vashisht et al. (2009) found that a SKP1 (
601434)-CUL1 (
603134)-FBXL5 (
605655) ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus. Thus, Vashisht et al. (2009) concluded that iron homeostasis is regulated by a proteolytic pathway that couples IRP2 degradation to intracellular iron levels through the stability and activity of FBXL5. Salahudeen et al. (2009) independently found that the E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation. The stability of FBXL5 itself was regulated, accumulating under iron- and oxygen-replete conditions and degraded upon iron depletion. FBXL5 contains an iron- and oxygen-binding hemerythrin domain that acted as a ligand-dependent regulatory switch mediating FBXL5's differential stability. Salahudeen et al. (2009) concluded that these observations suggested a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation, and cellular responses to maintain mammalian iron homeostasis.
MAPPING
By Southern analysis of somatic cell hybrid DNAs, Rouault et al. (1990) assigned the IREB2 gene to chromosome 15. For discussion of a possible association between variation in the IREB2 gene and chronic obstructive pulmonary disease, see
606963.
ANIMAL MODEL
LaVaute et al. (2001) showed that in mice, targeted disruption of the Ireb2 gene resulted in misregulation of iron metabolism in the intestinal mucosa and neurodegenerative disease of the central nervous system. In adulthood, Ireb2 -/- mice developed a movement disorder characterized by ataxia, bradykinesia, and tremor. Significant accumulations of iron in white m ...
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June 30, 2020: Protein entry updated
Automatic update: OMIM entry 147582 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).