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Thorsten Burmester - One of the best experts on this subject based on the ideXlab platform.
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The cellular and subcellular localization of Neuroglobin and cytoglobin -- a clue to their function?
IUBMB life, 2020Co-Authors: Thomas Hankeln, Stefan Reuss, Sylvia Wystub, Tilmann Laufs, Sigrid Saaler-reinhardt, Marc Schmidt, Frank Gerlach, Thorsten BurmesterAbstract:Neuroglobin and cytoglobin are recently discovered respiratory proteins of vertebrates with yet ill-defined physiological functions. Neuroglobin is widely expressed in neurons, but not glia, in the vertebrate central and peripheral nervous systems. Other major expression sites are the retina and endocrine tissues. This distribution is indicative of a function of Neuroglobin in metabolically most active, oxygen-consuming cell types, but does not yet allow to safely distinguish between different cellular roles, such as oxygen homeostasis, scavenging of reactive oxygen species or sustaining energy metabolism. Cytoglobin is predominantly expressed in connective tissue fibroblasts and related cell types in the body organs. Its main function may therefore be related to the specific amounts of extracellular matrix. Cytoglobin may hypothetically be involved in the oxygen-consuming maturation of collagen proteins. Cytoglobin is also expressed in distinct cell types of brain and retina. Its distribution strikingly differs from Neuroglobin, suggesting an independent, yet unknown function.
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The human brain hexacoordinated Neuroglobin three-dimensional structure.
Micron (Oxford England : 1993), 2020Co-Authors: Alessandra Pesce, Luc Moens, Sylvia Dewilde, Thomas Hankeln, Thorsten Burmester, M Nardini, Paolo Ascenzi, Martino BolognesiAbstract:Neuroglobin, mainly expressed in vertebrate brain and retina, is a recently identified member of the globin superfamily. Augmenting O2 supply, Neuroglobin promotes survival of neurons upon hypoxic injury, potentially limiting brain damage. In the absence of exogenous ligands, Neuroglobin displays a six-coordinated heme. O2 and CO bind to the heme-iron, displacing the endogenous HisE7 heme distal ligand. Hexacoordinated human Neuroglobin displays a classical globin fold, adapted to host the reversible bis-histidyl heme complex, and an elongated protein matrix cavity, held to facilitate O2 diffusion to the heme. The structure of Neuroglobin suggests that the classical globin fold is endowed with striking adaptability, indicating that hemoglobin and myoglobin are just two examples within a wide and functionally diversified protein homology superfamily.
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Neuroglobin Expression in the Mammalian Auditory System
Molecular Neurobiology, 2016Co-Authors: Stefan Reuss, Ovidiu Banica, Mirra Elgurt, Stephanie Mitz, Ursula Disque-kaiser, Randolf Riemann, Marco Hill, Dawn V. Jaquish, Fred J. Koehrn, Thorsten BurmesterAbstract:The energy-yielding pathways that provide the large amounts of metabolic energy required by inner ear sensorineural cells are poorly understood. Neuroglobin (Ngb) is a neuron-specific hemoprotein of the globin family, which is suggested to be involved in oxidative energy metabolism. Here, we present quantitative real-time reverse transcription PCR, in situ hybridization, immunohistochemical, and Western blot evidence that Neuroglobin is highly expressed in the mouse and rat cochlea. For primary cochlea neurons, Ngb expression is limited to the subpopulation of type I spiral ganglion cells, those which innervate inner hair cells, while the subpopulation of type II spiral ganglion cells which innervate the outer hair cells do not express Ngb. We further investigated Ngb distribution in rat, mouse, and human auditory brainstem centers, and found that the cochlear nuclei and superior olivary complex (SOC) also express considerable amounts of Ngb. Notably, the majority of olivocochlear neurons, those which provide efferent innervation of outer hair cells as identified by neuronal tract tracing, were Ngb-immunoreactive. We also observed that Neuroglobin in the SOC frequently co-localized with neuronal nitric oxide synthase, the enzyme responsible for nitric oxide production. Our findings suggest that Neuroglobin is well positioned to play an important physiologic role in the oxygen homeostasis of the peripheral and central auditory nervous system, and provides the first evidence that Ngb signal differentiates the central projections of the inner and outer hair cells.
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Neuroglobin of seals and whales: Evidence for a divergent role in the diving brain
Neuroscience, 2012Co-Authors: Marco Schneuer, S. Flachsbarth, Nicole U. Czech-damal, Lars P. Folkow, Ursula Siebert, Thorsten BurmesterAbstract:Abstract Although many physiological adaptations of diving mammals have been reported, little is known about how their brains sustain the high demands for metabolic energy and thus O 2 when submerged. A recent study revealed in the deep-diving hooded seal ( Cystophora cristata ) a unique shift of the oxidative energy metabolism and Neuroglobin, a respiratory protein that is involved in neuronal hypoxia tolerance, from neurons to astrocytes. Here we have investigated Neuroglobin in another pinniped species, the harp seal ( Pagophilus groenlandicus ), and in two cetaceans, the harbor porpoise ( Phocoena phocoena ) and the minke whale ( Balaenoptera acutorostrata ). Neuroglobin sequences, expression levels and patterns were compared with those of terrestrial relatives, the ferret ( Mustela putorius furo ) and the cattle ( Bos taurus ), respectively. Neuroglobin sequences of whales and seals only differ in two or three amino acids from those of cattle and ferret, and are unlikely to confer functional differences, e.g. in O 2 affinity. Neuroglobin is expressed in the astrocytes also of P. groenlandicus , suggesting that the shift of Neuroglobin and oxidative metabolism is a common adaptation in the brains of deep-diving phocid seals. In the cetacean brain Neuroglobin resides in neurons, like in terrestrial mammals. However, Neuroglobin mRNA expression levels were 4–15 times higher in the brains of harbor porpoises and minke whales than in terrestrial mammals or in seals. Thus Neuroglobin appears to play a specific role in diving mammals, but seals and whales have evolved divergent strategies to cope with cerebral hypoxia. The specific function of Neuroglobin that conveys hypoxia tolerance may either relate to oxygen supply or protection from reactive oxygen species. The different strategies in seals and whales resulted from a divergent evolution and an independent adaptation to diving.
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Ontogeny of globin expression in zebrafish (Danio rerio)
Journal of Comparative Physiology B, 2011Co-Authors: Jessica Tiedke, Thomas Hankeln, Frank Gerlach, Stephanie A. Mitz, Thorsten BurmesterAbstract:Respiratory proteins are responsible for transport and storage of oxygen. It is well established that specific requirements for oxygen during vertebrate ontogeny cause switches of hemoglobin chain expression. Here, we characterize the developmental profiles of zebrafish ( Danio rerio ) globins by means of quantitative real-time reverse transcription PCR. The total mRNA levels of the hemoglobin chains, including a newly identified embryonic α-chain, as well as myoglobin, Neuroglobin, cytoglobin 1 and 2, and globin X were estimated. mRNAs of all globins were detectable in unfertilized eggs, suggesting maternal storage. Embryonic α- and β-hemoglobin mRNA peaked at hatching and the switch to adult hemoglobin expression occurred 16 dpf. Enhanced myoglobin mRNA levels were detected ~31 h post-fertilization (hpf), coinciding with the heart and the muscle development, while Neuroglobin mRNA expression pattern correlates with the formation of the nervous system. Amounts of myoglobin and Neuroglobin mRNA were similar within an order of magnitude throughout the ontogeny, tentatively supporting a respiratory role of Neuroglobin. Cytoglobin 2 mRNA levels increased gradually, whereas cytoglobin 1 mRNA levels increased strongly after ~31 hpf, which is in agreement with a function in cell proliferation. Globin X mRNA level was highest in oocytes, but low in later stages. Together, these data suggest a specific role for each globin, which are also associated with certain events in fish development.
Luc Moens - One of the best experts on this subject based on the ideXlab platform.
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The human brain hexacoordinated Neuroglobin three-dimensional structure.
Micron (Oxford England : 1993), 2020Co-Authors: Alessandra Pesce, Luc Moens, Sylvia Dewilde, Thomas Hankeln, Thorsten Burmester, M Nardini, Paolo Ascenzi, Martino BolognesiAbstract:Neuroglobin, mainly expressed in vertebrate brain and retina, is a recently identified member of the globin superfamily. Augmenting O2 supply, Neuroglobin promotes survival of neurons upon hypoxic injury, potentially limiting brain damage. In the absence of exogenous ligands, Neuroglobin displays a six-coordinated heme. O2 and CO bind to the heme-iron, displacing the endogenous HisE7 heme distal ligand. Hexacoordinated human Neuroglobin displays a classical globin fold, adapted to host the reversible bis-histidyl heme complex, and an elongated protein matrix cavity, held to facilitate O2 diffusion to the heme. The structure of Neuroglobin suggests that the classical globin fold is endowed with striking adaptability, indicating that hemoglobin and myoglobin are just two examples within a wide and functionally diversified protein homology superfamily.
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Is the heme pocket region modulated by disulfide-bridge formation in fish and amphibian Neuroglobins as in humans?
Biochimica et Biophysica Acta, 2013Co-Authors: Wendy Van Leuven, Bert Cuypers, Filip Desmet, Daniela Giordano, Cinzia Verde, Luc Moens, Sabine Van Doorslaer, Sylvia DewildeAbstract:Abstract Neuroglobin, a globin characterized by a bis-histidine ligation of the heme iron, has been identified in mammalian and non-mammalian vertebrates, including fish, amphibians and reptiles. In human Neuroglobin, the presence of an internal disulfide bond in the CD loop (CD7–D5) is found to modulate the ligand binding through a change in the heme pocket structure. Although the Neuroglobin sequences mostly display conserved Cys at positions CD7, D5 and G18/19, a number of exceptions are known. In this study, Neuroglobins from amphibian (Xenopus tropicalis) and fish (Chaenocephalus aceratus, Dissostichus mawsoni and Danio rerio) are investigated using electron paramagnetic resonance and optical absorption spectroscopy. All these Neuroglobins differ from human Neuroglobin in their Cys-positions. It is demonstrated that if disulfide bonds are formed in fish and amphibian Neuroglobins, the reduction of these bonds does not result in alteration of the heme pocket in these globins. Furthermore, it is shown that mutagenesis of the Cys residues of X. tropicalis Neuroglobin influences the protein structure. The amphibian Neuroglobin is also found to be more resistant to H2O2-induced denaturation than the other Neuroglobins under study, although all show an overall large stability in high concentrations of this oxidant. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.
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biophysical characterisation of Neuroglobin of the icefish a natural knockout for hemoglobin and myoglobin comparison with human Neuroglobin
PLOS ONE, 2012Co-Authors: Daniela Giordano, Wendy Van Leuven, Luc Moens, Ignacio Boron, Stefania Abbruzzetti, Francesco P Nicoletti, Flavio Forti, Stefano Bruno, C Christina H Cheng, Guido Di PriscoAbstract:The Antarctic icefish Chaenocephalus aceratus lacks the globins common to most vertebrates, hemoglobin and myoglobin, but has retained Neuroglobin in the brain. This conserved globin has been cloned, over-expressed and purified. To highlight similarities and differences, the structural features of the Neuroglobin of this colourless-blooded fish were compared with those of the well characterised human Neuroglobin as well as with the Neuroglobin from the retina of the red blooded, hemoglobin and myoglobin-containing, closely related Antarctic notothenioid Dissostichus mawsoni. A detailed structural and functional analysis of the two Antarctic fish Neuroglobins was carried out by UV-visible and Resonance Raman spectroscopies, molecular dynamics simulations and laser-flash photolysis. Similar to the human protein, Antarctic fish Neuroglobins can reversibly bind oxygen and CO in the Fe2+ form, and show six-coordination by distal His in the absence of exogenous ligands. A very large and structured internal cavity, with discrete docking sites, was identified in the modelled three-dimensional structures of the Antarctic Neuroglobins. Estimate of the free-energy barriers from laser-flash photolysis and Implicit Ligand Sampling showed that the cavities are accessible from the solvent in both proteins. Comparison of structural and functional properties suggests that the two Antarctic fish Neuroglobins most likely preserved and possibly improved the function recently proposed for human Neuroglobin in ligand multichemistry. Despite subtle differences, the adaptation of Antarctic fish Neuroglobins does not seem to parallel the dramatic adaptation of the oxygen carrying globins, hemoglobin and myoglobin, in the same organisms.
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anoxia or oxygen and glucose deprivation in sh sy5y cells a step closer to the unraveling of Neuroglobin and cytoglobin functions
Gene, 2007Co-Authors: Elke Fordel, Luc Moens, Liesbet Thijs, Wim Martinet, Dorien M Schrijvers, Sylvia DewildeAbstract:Abstract Several studies support the hypothesis that Neuroglobin and cytoglobin play a protective role against cell death when cellular oxygen supply is critical. Although the underlying molecular mechanisms are unknown, previous reports suggest that this protection can be realised by the fact that they act as ROS scavengers. In this study, expression of Neuroglobin and cytoglobin was evaluated in a human neuroblastoma cell line (SH-SY5Y) under conditions of anoxia or oxygen and glucose deprivation (OGD). The cells could survive prolonged anoxia without significant loss of viability. They became anoxia sensitive when deprived of glucose. OGD induced significant cell death after 16 h resulting in 54% dead cells after 32 h. Necrosis was the main process involved in OGD-induced cell death. After reoxygenation, apoptotic neurons became more abundant. Real-time quantitative PCR and Western blotting revealed that Neuroglobin and cytoglobin were upregulated, the former under OGD and the latter under anoxic conditions. Under OGD, cell survival was significantly reduced after inhibiting cytoglobin expression by transfection with antisense ODN. Moreover, cell survival was significantly enhanced by Neuroglobin or cytoglobin overexpression. When Neuroglobin or cytoglobin protein expression increased or decreased, the H2O2 level was found to be lower or higher, respectively. We conclude that Neuroglobin or cytoglobin act as ROS scavengers under ischemic conditions.
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Neuroglobin and cytoglobin expression in mice
FEBS Journal, 2007Co-Authors: Elke Fordel, Luc Moens, Liesbet Thijs, Sylvia DewildeAbstract:Although essentially unknown, several functions are hypothesized for Neuroglobin and cytoglobin, two new members of the globin family. In this article, we try to shed more light on their possible roles in hypoxia and detoxification of reactive oxygen species in vivo. The relative transcriptional changes of Neuroglobin and cytoglobin in a situation of chronic hypoxia in mice were examined using real-time quantitative PCR. The kinetics of the hypoxic expression of Neuroglobin (brain, eyes) and cytoglobin (brain, eyes, liver, heart, skeletal muscle) is organ-specific. Moreover, reactive oxygen species production is higher in liver than in the other tissues. In eyes, the negative correlation, after reoxygenation, between Neuroglobin protein level and H2O2 concentration is a first proof of a reactive oxygen species-scavenging function for Neuroglobin. In addition, apoptotic cell death after hypoxia is for the first time demonstrated in heart and liver.
Sylvia Dewilde - One of the best experts on this subject based on the ideXlab platform.
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The human brain hexacoordinated Neuroglobin three-dimensional structure.
Micron (Oxford England : 1993), 2020Co-Authors: Alessandra Pesce, Luc Moens, Sylvia Dewilde, Thomas Hankeln, Thorsten Burmester, M Nardini, Paolo Ascenzi, Martino BolognesiAbstract:Neuroglobin, mainly expressed in vertebrate brain and retina, is a recently identified member of the globin superfamily. Augmenting O2 supply, Neuroglobin promotes survival of neurons upon hypoxic injury, potentially limiting brain damage. In the absence of exogenous ligands, Neuroglobin displays a six-coordinated heme. O2 and CO bind to the heme-iron, displacing the endogenous HisE7 heme distal ligand. Hexacoordinated human Neuroglobin displays a classical globin fold, adapted to host the reversible bis-histidyl heme complex, and an elongated protein matrix cavity, held to facilitate O2 diffusion to the heme. The structure of Neuroglobin suggests that the classical globin fold is endowed with striking adaptability, indicating that hemoglobin and myoglobin are just two examples within a wide and functionally diversified protein homology superfamily.
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Neuroglobin Expression in the Brain: a Story of Tissue Homeostasis Preservation.
Molecular Neurobiology, 2018Co-Authors: Zoë P. Van Acker, Evi Luyckx, Sylvia DewildeAbstract:After its discovery in 2000, the notion grew that Neuroglobin, a neuronal specific heme protein, is involved in cytoprotection. To date, Neuroglobin levels have been positively correlated with a beneficial outcome in a plethora of neurotoxic insults, e.g., ischemic and traumatic brain injuries and Alzheimer’s disease. The first part of this review goes further into these changes of Neuroglobin expression upon different neuronal insults as well as the underlying regulation. In the second part, we shed light on the mechanisms by which Neuroglobin contributes to neuroprotection, being (i) the scavenging and detoxification of reactive oxygen/nitrogen species, (ii) the augmentation of the threshold for apoptosis initiation, (iii) its contribution to an anti-inflammatory milieu, and (iv) tissue regeneration. We also consider different Neuroglobin models to address as yet unanswered questions. Based on the recent findings and progress in the field, we invigorate the avenues of Neuroglobin in neurological ailments to increase in the coming years.
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Is the heme pocket region modulated by disulfide-bridge formation in fish and amphibian Neuroglobins as in humans?
Biochimica et Biophysica Acta, 2013Co-Authors: Wendy Van Leuven, Bert Cuypers, Filip Desmet, Daniela Giordano, Cinzia Verde, Luc Moens, Sabine Van Doorslaer, Sylvia DewildeAbstract:Abstract Neuroglobin, a globin characterized by a bis-histidine ligation of the heme iron, has been identified in mammalian and non-mammalian vertebrates, including fish, amphibians and reptiles. In human Neuroglobin, the presence of an internal disulfide bond in the CD loop (CD7–D5) is found to modulate the ligand binding through a change in the heme pocket structure. Although the Neuroglobin sequences mostly display conserved Cys at positions CD7, D5 and G18/19, a number of exceptions are known. In this study, Neuroglobins from amphibian (Xenopus tropicalis) and fish (Chaenocephalus aceratus, Dissostichus mawsoni and Danio rerio) are investigated using electron paramagnetic resonance and optical absorption spectroscopy. All these Neuroglobins differ from human Neuroglobin in their Cys-positions. It is demonstrated that if disulfide bonds are formed in fish and amphibian Neuroglobins, the reduction of these bonds does not result in alteration of the heme pocket in these globins. Furthermore, it is shown that mutagenesis of the Cys residues of X. tropicalis Neuroglobin influences the protein structure. The amphibian Neuroglobin is also found to be more resistant to H2O2-induced denaturation than the other Neuroglobins under study, although all show an overall large stability in high concentrations of this oxidant. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.
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reactions of ferrous Neuroglobin and cytoglobin with nitrite under anaerobic conditions
Journal of Inorganic Biochemistry, 2008Co-Authors: Morten Gjerning Petersen, Sylvia Dewilde, Angela FagoAbstract:Abstract Recent evidence suggests that the reaction of nitrite with deoxygenated hemoglobin and myoglobin contributes to the generation of nitric oxide and S-nitrosothiols in vivo under conditions of low oxygen availability. We have investigated whether ferrous Neuroglobin and cytoglobin, the two hexacoordinate globins from vertebrates expressed in brain and in a variety of tissues, respectively, also react with nitrite under anaerobic conditions. Using absorption spectroscopy, we find that ferrous Neuroglobin and nitrite react with a second-order rate constant similar to that of myoglobin, whereas the ferrous heme of cytoglobin does not react with nitrite. Deconvolution of absorbance spectra shows that, in the course of the reaction of Neuroglobin with nitrite, ferric Fe(III) heme is generated in excess of nitrosyl Fe(II)–NO heme as due to the low affinity of ferrous Neuroglobin for nitric oxide. By using ferrous myoglobin as scavenger for nitric oxide, we find that nitric oxide dissociates from ferrous Neuroglobin much faster than previously appreciated, consistently with the decay of the Fe(II)–NO product during the reaction. Both Neuroglobin and cytoglobin are S-nitrosated when reacting with nitrite, with Neuroglobin showing higher levels of S-nitrosation. The possible biological significance of the reaction between nitrite and Neuroglobin in vivo under brain hypoxia is discussed.
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anoxia or oxygen and glucose deprivation in sh sy5y cells a step closer to the unraveling of Neuroglobin and cytoglobin functions
Gene, 2007Co-Authors: Elke Fordel, Luc Moens, Liesbet Thijs, Wim Martinet, Dorien M Schrijvers, Sylvia DewildeAbstract:Abstract Several studies support the hypothesis that Neuroglobin and cytoglobin play a protective role against cell death when cellular oxygen supply is critical. Although the underlying molecular mechanisms are unknown, previous reports suggest that this protection can be realised by the fact that they act as ROS scavengers. In this study, expression of Neuroglobin and cytoglobin was evaluated in a human neuroblastoma cell line (SH-SY5Y) under conditions of anoxia or oxygen and glucose deprivation (OGD). The cells could survive prolonged anoxia without significant loss of viability. They became anoxia sensitive when deprived of glucose. OGD induced significant cell death after 16 h resulting in 54% dead cells after 32 h. Necrosis was the main process involved in OGD-induced cell death. After reoxygenation, apoptotic neurons became more abundant. Real-time quantitative PCR and Western blotting revealed that Neuroglobin and cytoglobin were upregulated, the former under OGD and the latter under anoxic conditions. Under OGD, cell survival was significantly reduced after inhibiting cytoglobin expression by transfection with antisense ODN. Moreover, cell survival was significantly enhanced by Neuroglobin or cytoglobin overexpression. When Neuroglobin or cytoglobin protein expression increased or decreased, the H2O2 level was found to be lower or higher, respectively. We conclude that Neuroglobin or cytoglobin act as ROS scavengers under ischemic conditions.
Thomas Hankeln - One of the best experts on this subject based on the ideXlab platform.
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The cellular and subcellular localization of Neuroglobin and cytoglobin -- a clue to their function?
IUBMB life, 2020Co-Authors: Thomas Hankeln, Stefan Reuss, Sylvia Wystub, Tilmann Laufs, Sigrid Saaler-reinhardt, Marc Schmidt, Frank Gerlach, Thorsten BurmesterAbstract:Neuroglobin and cytoglobin are recently discovered respiratory proteins of vertebrates with yet ill-defined physiological functions. Neuroglobin is widely expressed in neurons, but not glia, in the vertebrate central and peripheral nervous systems. Other major expression sites are the retina and endocrine tissues. This distribution is indicative of a function of Neuroglobin in metabolically most active, oxygen-consuming cell types, but does not yet allow to safely distinguish between different cellular roles, such as oxygen homeostasis, scavenging of reactive oxygen species or sustaining energy metabolism. Cytoglobin is predominantly expressed in connective tissue fibroblasts and related cell types in the body organs. Its main function may therefore be related to the specific amounts of extracellular matrix. Cytoglobin may hypothetically be involved in the oxygen-consuming maturation of collagen proteins. Cytoglobin is also expressed in distinct cell types of brain and retina. Its distribution strikingly differs from Neuroglobin, suggesting an independent, yet unknown function.
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The human brain hexacoordinated Neuroglobin three-dimensional structure.
Micron (Oxford England : 1993), 2020Co-Authors: Alessandra Pesce, Luc Moens, Sylvia Dewilde, Thomas Hankeln, Thorsten Burmester, M Nardini, Paolo Ascenzi, Martino BolognesiAbstract:Neuroglobin, mainly expressed in vertebrate brain and retina, is a recently identified member of the globin superfamily. Augmenting O2 supply, Neuroglobin promotes survival of neurons upon hypoxic injury, potentially limiting brain damage. In the absence of exogenous ligands, Neuroglobin displays a six-coordinated heme. O2 and CO bind to the heme-iron, displacing the endogenous HisE7 heme distal ligand. Hexacoordinated human Neuroglobin displays a classical globin fold, adapted to host the reversible bis-histidyl heme complex, and an elongated protein matrix cavity, held to facilitate O2 diffusion to the heme. The structure of Neuroglobin suggests that the classical globin fold is endowed with striking adaptability, indicating that hemoglobin and myoglobin are just two examples within a wide and functionally diversified protein homology superfamily.
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Ontogeny of globin expression in zebrafish (Danio rerio)
Journal of Comparative Physiology B, 2011Co-Authors: Jessica Tiedke, Thomas Hankeln, Frank Gerlach, Stephanie A. Mitz, Thorsten BurmesterAbstract:Respiratory proteins are responsible for transport and storage of oxygen. It is well established that specific requirements for oxygen during vertebrate ontogeny cause switches of hemoglobin chain expression. Here, we characterize the developmental profiles of zebrafish ( Danio rerio ) globins by means of quantitative real-time reverse transcription PCR. The total mRNA levels of the hemoglobin chains, including a newly identified embryonic α-chain, as well as myoglobin, Neuroglobin, cytoglobin 1 and 2, and globin X were estimated. mRNAs of all globins were detectable in unfertilized eggs, suggesting maternal storage. Embryonic α- and β-hemoglobin mRNA peaked at hatching and the switch to adult hemoglobin expression occurred 16 dpf. Enhanced myoglobin mRNA levels were detected ~31 h post-fertilization (hpf), coinciding with the heart and the muscle development, while Neuroglobin mRNA expression pattern correlates with the formation of the nervous system. Amounts of myoglobin and Neuroglobin mRNA were similar within an order of magnitude throughout the ontogeny, tentatively supporting a respiratory role of Neuroglobin. Cytoglobin 2 mRNA levels increased gradually, whereas cytoglobin 1 mRNA levels increased strongly after ~31 hpf, which is in agreement with a function in cell proliferation. Globin X mRNA level was highest in oocytes, but low in later stages. Together, these data suggest a specific role for each globin, which are also associated with certain events in fish development.
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what is the function of Neuroglobin
The Journal of Experimental Biology, 2009Co-Authors: Thorsten Burmester, Thomas HankelnAbstract:SUMMARY For a long time, haemoglobin and myoglobin had been assumed to represent the only globin types of vertebrates. In 2000, however, we discovered a third globin type by mining the genome sequence data. Based on a preferential expression in the nervous system, this globin is referred to as Neuroglobin. Despite nine years of research, its function is still uncertain and a number of hypotheses have been put forward. Neuroglobin enhances cell viability under hypoxia and under various types of oxidative stress in transgenic systems, but does not appear to be strongly upregulated in response to stress. A close phylogenetic relationship with invertebrate nerve globins and its positive correlation with the oxidative metabolism and mitochondria suggest a role in O 2 supply. In vitro studies and cell culture experiments imply that Neuroglobin may detoxify reactive oxygen or nitric oxide. Still other studies propose Neuroglobin as being part of a signalling chain that transmits the redox state of the cell or that inhibits apoptosis. Although some functions are more probable than others, we conclude that it is still too early to definitively decide what may be the physiological role(s) of Neuroglobin in vertebrates. Nevertheless, there is no doubt that Neuroglobin has an essential, conserved function and is beneficial to neurons.
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Neuroglobin and Other Nerve Haemoglobins
Dioxygen Binding and Sensing Proteins, 2008Co-Authors: Thorsten Burmester, Thomas HankelnAbstract:The nervous system of animals requires huge amounts of metabolic energy and thus oxygen. Intracellular haemoglobins sporadically occur in glial cells and neurons of various invertebrate taxa, including Annelida, Arthropoda, Echiura, Mollusca, Nematoda and Nemertea. At least some of these respiratory proteins sustain the aerobic metabolism and thus the excitability of the nervous system. Recently, we have identified Neuroglobin as an oxygen-binding protein of vertebrate neurons. The physiological role of Neuroglobin, which is apparently present in much lower amounts than many invertebrate nerve haemoglobins, is less well established. Phylogenetic analyses have shown that Neuroglobin is orthologous to at least some of the invertebrate respiratory proteins, while other invertebrate nerve globins may have divergent evolutionary origins. Functional changes thus appear to be common in animal globin evolution. The occurrence of yet other types of intracellular globins in nervous tissue of vertebrates is functionally unexplained and requires further studies.
Djemel Hamdane - One of the best experts on this subject based on the ideXlab platform.
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the crystal structure of wild type human brain Neuroglobin reveals flexibility of the disulfide bond that regulates oxygen affinity
Acta Crystallographica Section D-biological Crystallography, 2014Co-Authors: B G Guimaraes, Djemel Hamdane, Michael C Marden, Christophe Lechauve, Beatrice GolinellipimpaneauAbstract:Neuroglobin plays an important function in the supply of oxygen in nervous tissues. In human Neuroglobin, a cysteine at position 46 in the loop connecting the C and D helices of the globin fold is presumed to form an intramolecular disulfide bond with Cys55. Rupture of this disulfide bridge stabilizes bi-histidyl haem hexacoordination, causing an overall decrease in the affinity for oxygen. Here, the first X-ray structure of wild-type human Neuroglobin is reported at 1.74 A resolution. This structure provides a direct observation of two distinct conformations of the CD region containing the intramolecular disulfide link and highlights internal cavities that could be involved in ligand migration and/or are necessary to enable the conformational transition between the low and high oxygen-affinity states following S—S bond formation.
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zebrafish reveals different and conserved features of vertebrate Neuroglobin gene structure expression pattern and ligand binding
Journal of Biological Chemistry, 2004Co-Authors: Christine Fuchs, Thomas Hankeln, Valeska Heib, Laurent Kiger, Mark Haberkamp, Anja Roesner, Marc Schmidt, Djemel Hamdane, Michael C Marden, Thorsten BurmesterAbstract:Abstract 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.
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Coupling of the heme and an internal disulfide bond in human Neuroglobin
Micron, 2004Co-Authors: Djemel Hamdane, Sylvia Dewilde, Thomas Hankeln, Thorsten Burmester, Laurent Kiger, Alessandra Pesce, Martino Bolognesi, Brian N Green, Julien Uzan, Luc MoensAbstract:Abstract Neuroglobin displays a hexacoordination His-Fe-His in the absence of external ligands such as oxygen. The observed oxygen affinity therefore depends on the binding rates of both oxygen and the competing distal histidine. Furthermore, the binding properties depend on the presence of an internal disulfide bond. In the case of human Neuroglobin, cysteines at positions CD7 and D5 are sufficiently close to form an internal disulfide bond. For cytoglobin, the cysteine residues at positions A7 and GH4 may also form a disulfide bond. Mass spectrometry, ligand binding, and thiol accessibility studies were used to study the role influence of these disulfide bonds. Mutation of specific cysteines, or reduction to break the S–S bond, led to a large decrease in the observed oxygen affinity of human Neuroglobin, mainly due to a decrease in the histidine dissociation rate. This suggests a novel mechanism for the oxygen binding; reduction of the disulfide bond would provoke the release of oxygen.
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the redox state of the cell regulates the ligand binding affinity of human Neuroglobin and cytoglobin
Journal of Biological Chemistry, 2003Co-Authors: Djemel Hamdane, Sylvia Dewilde, Thomas Hankeln, Thorsten Burmester, Laurent Kiger, Alessandra Pesce, Martino Bolognesi, Brian N Green, Julien Uzan, Luc MoensAbstract:Abstract Neuroglobin and cytoglobin reversibly bind oxygen in competition with the distal histidine, and the observed oxygen affinity therefore depends on the properties of both ligands. In the absence of an external ligand, the iron atom of these globins is hexacoordinated. There are three cysteine residues in human Neuroglobin; those at positions CD7 and D5 are sufficiently close to form an internal disulfide bond. Both cysteine residues in cytoglobin, although localized in other positions than in human Neuroglobin, may form a disulfide bond as well. The existence and position of these disulfide bonds was demonstrated by mass spectrometry and thiol accessibility studies. Mutation of the cysteines involved, or the use of reducing agents to break the S–S bond, led to a decrease in the observed oxygen affinity of human Neuroglobin by an order of magnitude. The critical parameter is the histidine dissociation rate, which changes by about a factor of 10. The same effect is observed with human cytoglobin, although to a much lesser extent (less than a factor of 2). These results suggest a novel mechanism for the regulation of oxygen binding; contact with an appropriate electron donor would provoke the release of oxygen. Hence the oxygen affinity would be directly linked to the redox state of the cell.