A Globin in the Nucleus!

Geuens, Eva; Brouns, Inge; Flamez, Daisy; Dewilde, Sylvia; Timmermans, Jean‐Pierre; Moëns, Luc

doi:10.1074/jbc.c300203200

Cited by 147 publications

(149 citation statements)

References 48 publications

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“…Ngb in the Chloride Cells Suggests Another Association of Ngb with Mitochondria-With the exception of the expression in some endocrine tissues (19,20), Ngb has been assumed to be an exclusively neuronal protein. Here we show by immunofluorescence studies, ISH, and Western blotting that Ngb was also present in the chloride cells of zebrafish gills.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish Reveals Different and Conserved Features of Vertebrate Neuroglobin Gene Structure, Expression Pattern, and Ligand Binding

Fuchs

Heib

Kiger

et al. 2004

Journal of Biological Chemistry

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Neuroglobin has been identified as a respiratory protein that is primarily expressed in the mammalian nervous system. Here we present the first detailed analysis of neuroglobin from a non-mammalian vertebrate, the zebrafish Danio rerio. The zebrafish neuroglobin gene reveals a mammalian-type exon-intron pattern in the coding region (B12.2, E11.0, and G7.0), plus an additional 5-non-coding exon. Similar to the mammalian neuroglobin, the zebrafish protein displays a hexacoordinate deoxy-binding scheme. Flash photolysis kinetics show the competitive binding on the millisecond timescale of external ligands and the distal histidine, resulting in an oxygen affinity of 1 torr. Western blotting, immune staining, and mRNA in situ hybridization demonstrate neuroglobin expression in the fish central nervous system and the retina but also in the gills. Neurons containing neuroglobin have a widespread distribution in the brain but are also present in the olfactory system. In the fish retina, neuroglobin is mainly present in the inner segments of the photoreceptor cells. In the gills, the chloride cells were identified to express neuroglobin. Neuroglobin appears to be associated with mitochondria-rich cell types and thus oxygen consumption rates, suggesting a myoglobin-like function of this protein in facilitated oxygen diffusion.Transport and storage of oxygen in vertebrate animals are typically mediated by globins, small proteins that bind O 2 by the means of a porphyrin-coordinated Fe 2ϩ ion (1-3). The heterotetrameric hemoglobin is present in red blood cells of nearly all vertebrates and transports O 2 in the circulatory system from the respiratory surfaces to the inner organs. The monomeric myoglobin, typically found in the myocytes of cardiac and striated muscles, facilitates intracellular O 2 diffusion to the mitochondria and stores O 2 (3, 4) but also functions as an nitric-oxide dioxygenase (5). Neuroglobin (Ngb) 1 and cytoglobin are two recently discovered vertebrate globins (6 -9). Whereas cytoglobin might play a role in collagen synthesis (10, 11), the leading hypotheses suggest Ngb to be involved in neuronal oxygen homeostasis (6,(12)(13)(14)(15)(16). Ngb shares only a few amino acids with vertebrate hemoglobin and myoglobin (Ͻ25% identity) but rather resembles the nerve-specific globins known in some invertebrates (6, 13). In fact, phylogenetic analyses suggest an ancient origin of Ngb, probably diverging from the other globins before the Protostomia-Deuterostomia split (6, 8). Mouse and human deoxy-Ngb display hexacordinated hemochrome-binding schemes at the Fe 2ϩ (17, 18). The proximal histidine can be replaced by an external ligand such as O 2 , resulting in an oxygen affinity (P 50 ) of ϳ1-2 torr, similar to that of myoglobin (6, 17).Initially, Ngb was found to be predominantly expressed in the brains of man and mouse (6), but recent analyses show Ngb to be also present in the peripheral nervous system and some non-neuronal endocrine tissues (19 -21). Particularly high amounts of Ngb were observed in the m...

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Section: Discussionmentioning

confidence: 99%

Zebrafish Reveals Different and Conserved Features of Vertebrate Neuroglobin Gene Structure, Expression Pattern, and Ligand Binding

Fuchs

Heib

Kiger

et al. 2004

Journal of Biological Chemistry

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“…Immunocytochemistry studies showed that cytoglobin is located in the cytoplasm in mouse connective tissues, and nucleus as well as cytoplasm of neurons, implying the respiratory function (Schmidt et al 2004). Moreover, the nuclear location of cytoglobin in mouse neural and endocrine cells was also reported (Geuens et al 2003). When human cytoglobin was expressed in Cos7 cells, the protein in some cells was exclusively localized to the nucleus and in others to the cytoplasm and nucleus (J. Matsubara and S. Taketani, unpublished data), indicating that the localization of cytoglobin changed, dependent on conditions of cells.…”

Section: Contribution Of Iron and Heme To Oxygen-sensing Systemmentioning

confidence: 98%

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

100

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Iron is fastidiously utilized by living cells, since it is an essential element, but is toxic in excess. Cells take up iron via a transferrin-transferrin receptor-dependent endocytotic process. The iron thus taken up is used for essential biological functions including oxygen transport, electron transfer, and DNA synthesis. The intracellular level of iron is tightly controlled, through regulation of the cellular uptake of iron and the sequestering of low molecular labile iron into the storage protein ferritin. The known proteins of iron transport and storage, transferrin, transferrin receptor and ferritin, have been recently linked with a number of newly identified proteins that are responsible for inherited diseases of iron metabolisms and play critical roles in the maintenance of iron homeostasis. These proteins are involved in regulation of intracellular levels of iron, iron transport, and heme transport and the oxygen-dependent regulation of gene expression. On the other hand, most iron is transported into mitochondria and immediately used for the biosynthesis of heme in erythroid cells. The heme biosynthesis in mitochondria is coupled with the supply of iron, and the heme, exported from mitochondria, is utilized as prosthetic groups of hemeproteins. Furthermore, non-erythroid and erythroid cells possess the different regulatory systems for the biosynthesis of heme; iron positively regulates the biosynthesis in erythroid cells while heme negatively regulates it in non-erythroid cells. Because of the toxicity and insolubility of heme, the intracellular level of uncommitted heme is maintained at a low concentration (< 10 -9 M). The influx and efflux of heme also help to prevent cytotoxicity. Finally, heme-binding transcriptional factors such as Bach1 and NPAS2 regulate the transcription of several genes involved in the synthesis and degradation of heme-hemeproteins. The discovery of new molecules related to disorders of iron and heme metabolism is ascribable to a complete mechanistic understanding of the cellular network of iron homeostasis. The network of interactions that link iron and heme metabolisms with functions of cellular regulation involving oxidative stress and inflammations contributes to new insights into clinical aspects of disorders.

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“…These two hydroxylases are localized in the nucleus and in the cytoplasm, respectively. Interestingly, CYGB has been localized in the nucleus and in the cytoplasm (5,54) and is up-regulated during hypoxia (21).…”

Section: On the Reaction Of 4-pds With Ngb And Human Hbamentioning

confidence: 99%

Allosteric Regulation and Temperature Dependence of Oxygen Binding in Human Neuroglobin and Cytoglobin

Fago

Hundahl

Dewilde

et al. 2004

Journal of Biological Chemistry

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172

225

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Two new globin proteins have recently been discovered in vertebrates, neuroglobin in neurons and cytoglobin in all tissues, both showing heme hexacoordination by the distal His(E7) in the absence of gaseous ligands. In analogy to hemoglobin and myoglobin, neuroglobin and cytoglobin are supposedly involved in O 2 storage and delivery, although their physiological role remains to be solved. Here we report O 2 equilibria of recombinant human neuroglobin (NGB) and cytoglobin (CYGB) measured under close to physiological conditions and at varying temperature and pH ranges. NGB shows both alkaline and acid Bohr effects (pH-dependent O 2 affinity) and temperature-dependent enthalpy of oxygenation. O 2 and CO binding equilibrium studies on neuroglobin mutants strongly suggest that the bound O 2 is stabilized by interactions with His(E7) and that this residue functions as a major Bohr group in the presence of Lys(E10). As shown by the titration of free thiols with 4,4 -dithiodipyridine and by mass spectrometry, this mechanism of modulating O 2 affinity is independent of formation of an internal disulfide bond under the experimental conditions used, which stabilize thiols in the reduced form. In CYGB, O 2 binding is cooperative, consistent with its proposed dimeric structure. Similar to myoglobin but in contrast to NGB, O 2 binding to CYGB is pH-independent and exothermic throughout the temperature range investigated. Our data support the hypothesis that CYGB may be involved in O 2 -requiring metabolic processes. In contrast, the lower O 2 affinity in NGB does not appear compatible with a physiological role involving mitochondrial O 2 supply at the low O 2 tensions found within neurons.

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A Globin in the Nucleus!

Cited by 147 publications

References 48 publications

Zebrafish Reveals Different and Conserved Features of Vertebrate Neuroglobin Gene Structure, Expression Pattern, and Ligand Binding

Zebrafish Reveals Different and Conserved Features of Vertebrate Neuroglobin Gene Structure, Expression Pattern, and Ligand Binding

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Allosteric Regulation and Temperature Dependence of Oxygen Binding in Human Neuroglobin and Cytoglobin

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