Human iron regulatory protein 2 is easily cleaved in its specific domain: consequences for the haem binding properties of the protein

Dycke, Camille; Bougault, Catherine; Gaillard, Jacques; Andrieu, Jean-Pierre; Pantopoulos, Kostas; Moulis, Jean‐Marc

doi:10.1042/bj20070983

Cited by 24 publications

(21 citation statements)

References 42 publications

(57 reference statements)

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“…The broad Soret band for the heme bound Irr also corresponds to multiple configurations of heme binding in Irr. Such a broad Soret band was also reported for the HRM containing heme-regulated proteins such as Hap1 (23), Bach1 (24), and IRP2 (12, 25). The ligation of 29 Cys to the heme iron is, therefore, heterogeneous and distinct from the conventional Cys-ligated hemoproteins, which is characteristic for heme-regulated proteins with the HRM.…”

Section: Resultssupporting

confidence: 63%

Unusual Heme Binding in the Bacterial Iron Response Regulator Protein: Spectral Characterization of Heme Binding to the Heme Regulatory Motif

et al. 2011

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Section: Resultssupporting

confidence: 63%

Unusual Heme Binding in the Bacterial Iron Response Regulator Protein: Spectral Characterization of Heme Binding to the Heme Regulatory Motif

et al. 2011

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“…IRP2 binds a Cys-ligated heme in a HRM, and heme binding underpins its iron-sensing mechanism (19). Heme may bind only to a truncated IRP2 that is specifically proteolyzed as part of the regulatory mechanism (20). However, another proposal is that C-terminal cysteines bind iron directly and that heme has no role in IRP2 degradation (21).…”

Section: Iron Heme and Oxidative Stress Responsementioning

confidence: 99%

Heme Sensor Proteins

Girvan

Munro

2013

Journal of Biological Chemistry

128

116

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Heme is a prosthetic group best known for roles in oxygen transport, oxidative catalysis, and respiratory electron transport. Recent years have seen the roles of heme extended to sensors of gases such as O 2 and NO and cell redox state, and as mediators of cellular responses to changes in intracellular levels of these gases. The importance of heme is further evident from identification of proteins that bind heme reversibly, using it as a signal, e.g. to regulate gene expression in circadian rhythm pathways and control heme synthesis itself. In this minireview, we explore the current knowledge of the diverse roles of heme sensor proteins. Heme-responsive Proteins: Defining FeaturesHeme homeostasis is crucial. Free heme at Ͼ1 M is cytotoxic, mainly by producing reactive oxygen species. Iron intake accounts for only a small proportion of mammalian requirements, so iron recycling (particularly from heme) is critical (1). Tight regulation of heme synthesis/breakdown is needed. Heme regulates its own fate and controls several other biological processes. Heme-responsive proteins elicit cellular responses by binding/debinding heme or via changes in heme ligation (e.g. by gases) or redox state. They can be divided into two classes: nuclear receptor (NR) 2 hemoproteins and heme sensors with no NR function. Each heme-responsive protein has a heme regulatory motif (HRM), usually containing a CP motif (2). The Cys residue of the CP motif is an axial heme ligand. No other residues are conserved across the protein class. The wider relevance of the CP motif is unclear because other hemoproteins (e.g. prostaglandin E 2 synthase, chloroperoxidase, and some cytochromes P450) also have a CP motif. The properties of members of the two main classes are described below. NR HemoproteinsSeveral heme-binding proteins occur in the NR superfamily, which is the largest transcription factor superfamily (summarized in Table 1). NRs bind specific DNA motifs in response to small molecule signaling. They generally share conserved domain architecture, with a DNA-binding region containing two zinc fingers, a ligand-binding domain, and activation domains (3). Usually, ligand binding induces conformational changes that dissociate partner proteins, allowing DNA binding and/or changes to dimerization status or cellular localization that enable the protein to elicit a response. A subfamily of NRs binds heme at their ligand-binding domain and so act as heme sensors, as discussed below. Circadian Rhythm Heme SensorsCircadian rhythms are regulated by feedback loops at transcriptional/translational levels. Heme is critical in this process (4). In vertebrates, the expression of several day/night cycle genes, as well as Rev-erb␣, is controlled by binding a heterodimer of Clock (or NPAS2 (neuronal PAS domain protein 2)) and Bmal1 to their 5Ј-UTR, thus switching on transcription. Expression of Bmal1 and NPAS2/Clock is repressed in turn by binding of Rev-erb␣ to a homodimeric partner (5). Rev-erb␣ and homologs (Rev-erb␤ and E75, with the latter involved in inse...

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“…However, a mutant IRP2 protein lacking this 73-amino acid region degraded at a rate similar to that of wild-type IRP2 (106). Dycke et al, (2007) showed this sequence is an active non-iron dependent cleavage domain in cultured breast cancer cells, and that it is unlikely that the iron-dependent degradation of IRP2 is mediated by haem binding to the intact 73 aa domain (107). These results are relevant to AD since oxidative stress is important during AD and the APP mRNA has an active IRE in its 5′UTR (Figure 4).…”

Section: B Ferritin Translational Control: Links To App and Asyn Mrnmentioning

confidence: 99%

Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases

Cahill

Lahiri

Huang

et al. 2009

Biochimica et Biophysica Acta (BBA) - General Subjects

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Summary Recent studies that alleles in the hemochromatosis gene may accelerate the onset of Alzheimer's disease (AD) by five years have validated interest in the model in which metals (particularly iron) accelerate disease course. Biochemical and biophysical measurements demonstrated the presence of elevated levels of neurotoxic copper, zinc and iron in the brains of AD patients. Intracellular levels of amyloid precursor protein (APP) holoprotein were shown to be modulated via iron by a mechanism that is similar to the translation control of the ferritin L- and H mRNAs by Iron-responsive Element (IRE) RNA stem loops in their 5′untranslated regions (5′UTRs). Recently, we reported a putative IRE-like sequence to be present in the 5′UTR of the Parkinson's disease (PD) specific alpha synuclein (ASYN) transcript. ASYN encodes the non-Aβ component (NAC) of amyloid plaques. The demonstration of iron-dependent translation of APP mRNA, the involvement of metals in the plaque of AD patients and of increased iron in striatal neurons in the Substantia nigra (SN) of PD patients, have each encouraged the development of metal attenuating agents and iron chelators as a major new therapeutic strategy for the treatment of these neurodegenerative diseases. In the case of AD, metal based therapeutics may ultimately prove more cost effective than the use of an amyloid vaccine as the preferred anti-amyloid therapeutic strategy to ameliorate the cognitive decline of AD patients.

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Human iron regulatory protein 2 is easily cleaved in its specific domain: consequences for the haem binding properties of the protein

Cited by 24 publications

References 42 publications

Unusual Heme Binding in the Bacterial Iron Response Regulator Protein: Spectral Characterization of Heme Binding to the Heme Regulatory Motif

Unusual Heme Binding in the Bacterial Iron Response Regulator Protein: Spectral Characterization of Heme Binding to the Heme Regulatory Motif

Heme Sensor Proteins

Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases

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