Differences in the RNA binding sites of iron regulatory proteins and potential target diversity.

Butt, Julea N.; Kim, Hae Yeong; Basilion, James P.; Cohen, Seth M.; Iwaï, Kazuhiro; Philpott, Caroline C.; Altschul, Stephen F.; Klausner, Richard D.; Rouault, Tracey A.

doi:10.1073/pnas.93.9.4345

Cited by 141 publications

(124 citation statements)

References 38 publications

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“…Replacement of the consensus adenine with guanosine might alter the orientation of this stacking interaction, but such a change is unlikely to produce a large ⌬⌬G 25 (complex). Although SELEX experiments have confirmed the preference for adenosine at this site, one study found cytidine in several IRP-binding clones and guanosine in a single IRP2-specific sequence containing multiple nonconsensus nucleotides (23), whereas the other identified cytidine-and uridine-containing sequences (24). The tolerance of substitutions other than guanosine at this site suggests that this nucleobase may be involved in a stacking interaction with the IRP and that the large size of guanosine may disrupt this association under most conditions.…”

Section: Discussionmentioning

confidence: 99%

“…We also found that with every mutation, except Pavia 2, the affinity for IRP1 was more affected than for IRP2. Studies of nonconsensus IRP-binding sequences have shown that, in general, IRP2 has a greater tolerance for mutations within the hexanucleotide loop of the IRE (23,24). Additionally, the IRE binding capacity of IRP2 is much less affected by mutagenesis of individual arginines within the putative IRE-binding site (23).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of nonconsensus IRP-binding sequences have shown that, in general, IRP2 has a greater tolerance for mutations within the hexanucleotide loop of the IRE (23,24). Additionally, the IRE binding capacity of IRP2 is much less affected by mutagenesis of individual arginines within the putative IRE-binding site (23). The diminished sensitivity of IRP2 to IRE mutations is b Cataract was judged severe when there was a marked loss in visual acuity in the 1st decades (with some individuals requiring surgery), mild when the defect in visual acuity could be corrected with the use of appropriate eyeglasses, and asymptomatic when it did not impair visual acuity.…”

Section: Discussionmentioning

confidence: 99%

“…We were also interested in evaluating whether HHCS mutations might affect the affinities of IRP1 and IRP2 differently. As studies have demonstrated, both IRP1 and IRP2 are capable of recognizing their own unique substrates in vitro (23,24). In an effort to identify any corre-lation between HHCS severity and IRP affinity, and to reveal any differences in the behavior of the two IRPs, we determined the dissociation constants (K D values) for the binding of the HHCS IREs to both IRP1 and IRP2.…”

Section: Several Reports Have Described a New Autosomal Dominant Disomentioning

confidence: 99%

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Clinical Severity and Thermodynamic Effects of Iron-responsive Element Mutations in Hereditary Hyperferritinemia-Cataract Syndrome

Allerson¹,

Cazzola²,

Rouault³

1999

Journal of Biological Chemistry

114

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Hereditary hyperferritinemia-cataract syndrome (HHCS) is a novel genetic disorder characterized by elevated serum ferritin and early onset cataract formation. The excessive ferritin production in HHCS patients arises from aberrant regulation of L-ferritin translation caused by mutations within the ironresponsive element (IRE) of the L-ferritin transcript. IREs serve as binding sites for iron regulatory proteins (IRPs), iron-sensing proteins that regulate ferritin translation. Previous observations suggested that each unique HHCS mutation conferred a characteristic degree of hyperferritinemia and cataract severity in affected individuals. Here we have measured the in vitro affinity of the IRPs for the mutant IREs and correlated decreases in binding affinity with clinical severity. Thermodynamic analysis of these IREs has also revealed that although some HHCS mutations lead to changes in the stability and secondary structure of the IRE, others appear to disrupt IRP-IRE recognition with minimal effect on IRE stability. HHCS is a noteworthy example of a human genetic disorder that arises from mutations within a protein-binding site of an mRNA cis-acting element. Analysis of the effects of these mutations on the energetics of the RNA-protein interaction explains the phenotypic variabilities of the disease state. Several reports have described a new autosomal dominant disorder called hereditary hyperferritinemia-cataract syndrome (HHCS)1 (1-12). This condition is characterized by a combination of elevated levels of serum ferritin and congenital nuclear cataract. Human ferritin is composed of two different types of subunit (H-ferritin and L-ferritin), although the relative proportion of each subunit in the ferritin copolymer varies among tissues (13). Through the use of monoclonal antibodies specific for either H-or L-ferritin, the excess serum ferritin in HHCS patients has been shown to be predominantly L-ferritin (3, 7). A close relationship has also been established between monocyte L-ferritin content and serum ferritin concentration (7), suggesting that the excess production of L-ferritin in cells is directly responsible for the hyperferritinemia. Although serum ferritin is thought to reflect body iron stores, individuals with HHCS do not appear to suffer from iron overload (1, 2).The expression of both H-ferritin and L-ferritin is normally regulated according to intracellular iron concentration by means of iron-responsive elements (IREs) that are found within the 5Ј-untranslated regions of their transcripts (14, 15). These regulatory elements interact with the iron regulatory proteins IRP1 and IRP2, which are both capable of sensing cellular iron status. Under conditions of intracellular iron depletion, both IRP1 and IRP2 bind to IREs with high affinity. The binding of an IRP to the ferritin IRE prevents the binding of the 43 S translation initiation complex to the transcript (16, 17) and thus blocks translation of the ferritin protein. When intracellular iron concentrations rise, IRP1 acquires a [4Fe-4S] cluster ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Several Reports Have Described a New Autosomal Dominant Disomentioning

confidence: 99%

See 2 more Smart Citations

Clinical Severity and Thermodynamic Effects of Iron-responsive Element Mutations in Hereditary Hyperferritinemia-Cataract Syndrome

Allerson¹,

Cazzola²,

Rouault³

1999

Journal of Biological Chemistry

114

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“…However, when iron is abundant, a conformational change in IRP-1 prevents its interaction with the IREs and degradation of IRP-2 is increased. 5 In the absence of the negative regulatory influence of the IRPs, the (mRNA)FTL and (mRNA)FTH are translated constitutively and apoferritin is synthesised. 3 Hereditary hyperferritinaemia cataract syndrome (HHCS; OMIM 600886) is an autosomal dominant disorder of ferritin synthesis characterised by early onset cataracts and increased serum concentration of L-ferritin.…”

Section: Introductionmentioning

confidence: 99%

Clinical features and molecular analysis of seven British kindreds with hereditary hyperferritinaemia cataract syndrome

Lachlan¹,

Temple²,

Mumford

2004

Eur J Hum Genet

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Hereditary hyperferritinaemia cataract syndrome (HHCS) is an autosomal dominant disorder characterised by early onset cataracts and increased serum L-ferritin concentration. Affected individuals show nucleotide substitutions in the region of the L-ferritin gene (FTL) that encodes a regulatory sequence within the (mRNA)FTL termed the iron responsive element (IRE). We report the clinical features of seven HHCS kindreds containing 49 individuals with premature cataract. All the probands received diagnoses of HHCS after the incidental discovery of increased serum L-ferritin concentration (median 1420 lg/l; normal range 15 -360 lg/l), in most cases during investigation or screening for anaemia. All the probands developed characteristic 'sunflower' morphology cataracts in childhood (median age at diagnosis 5 years), but had no other phenotypic features. All the affected kindreds showed nucleotide substitutions in FTL that were predicted to disrupt function of the (mRNA)FTL IRE. The severity of the clinical phenotype of HHCS was variable both within and between kindreds and showed no clear relationship to FTL genotype. HHCS should be included in the differential diagnosis of hyperferritinaemia and should be carefully distinguished from hereditary haemochromatosis. Measurement of the serum L-ferritin concentration should be included in the investigation of all individuals with early onset cataracts.

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Cytosolic Aconitase

Volbeda

Moulis

Dupuy

et al. 2004

Handbook of Metalloproteins

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Cytosolic aconitases (cAcns) have the remarkable property that they can function either as an enzyme or as a messenger (m) RNA‐binding protein. In the first case they contain a [4Fe–4S] cluster that is directly involved in the catalysis of the isomerization between citrate and isocitrate via a cis ‐aconitate intermediate. Upon loss of the cluster the enzymatic function is lost, the protein undergoes a substantial structural rearrangement and becomes capable of recognizing, with very high affinity, the so‐called iron‐responsive elements (IREs) in mRNAs. The latter code for proteins that are either dependent on Fe or are involved in the regulation of iron levels in the cell. The nonenzymatic form of cAcn is known as iron‐regulatory protein 1 or IRP1. Here we review the most recent structural data on the two forms, cAcn and IRP1, and correlate these with their respective functional properties. In addition, a comparison is made with closely related proteins like IRP2 and mitochondrial and bacterial aconitases.

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Differences in the RNA binding sites of iron regulatory proteins and potential target diversity.

Abstract: Posttranscriptional regulation of genes of mammalian iron metabolism is mediated by the interaction of iron regulatory proteins (IRPs) with RNA stem-loop sequence elements known as iron-responsive elements (IREs)

Cited by 141 publications

References 38 publications

Clinical Severity and Thermodynamic Effects of Iron-responsive Element Mutations in Hereditary Hyperferritinemia-Cataract Syndrome

Clinical Severity and Thermodynamic Effects of Iron-responsive Element Mutations in Hereditary Hyperferritinemia-Cataract Syndrome

Clinical features and molecular analysis of seven British kindreds with hereditary hyperferritinaemia cataract syndrome

Cytosolic Aconitase

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