(The FASEB Journal. 2006;20:2192-2197.)
© 2006 FASEB
A Globin for the Brain
M. Brunori1 and
B. Vallone
Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Biochemical Sciences, University of Rome "La Sapienza," Rome, Italy
1Correspondence: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli," Università di Roma "La Sapienza," Piazzale A. Moro 5, 00185 Rome, Italy. E-mail: maurizio.brunori{at}uniroma1.it
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ABSTRACT
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The discovery that a myoglobin-like hemeprotein (called neuroglobin) is expressed in our brain raised considerable curiosity from the standpoints of biochemistry and pathophysiology alike. Neuroglobin is involved in neuroprotection from damage due to hypoxia or ischemia in vitro and in vivo; overexpression of neuroglobin ameliorates the recovery from stroke in experimental animals. The mechanism underlying this remarkable effect is still mysterious. Structural studies revealed that neuroglobin has a typical globin fold, and despite being hexacoordinated, it binds reversibly O2, CO, and NO, undergoing a substantial conformational change of the heme and of the protein. The possible mechanisms involved in neuroprotection are briefly reviewed. Neuroglobin is unlikely to be involved in O2 transport (like myoglobin), although it seems to act as a sensor of the O2/NO ratio in the cell, possibly regulating the GDP/GTP exchange rate forming a specific complex with the G
ß
-protein when oxidized but not when bound to a gaseous ligand. Thus it appears that neuroglobin is a stress-responsive sensor for signal transduction in the brain, mediated by a ligand-linked conformational change of the protein.—Brunori, M., Vallone, B. A globin for the brain.
Key Words: neuroprotection • O2/NO binding • structure
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INTRODUCTION
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UNTIL A FEW YEARS AGO, it was taken for granted that the human body contains only two globins, which are essential for O2 supply to tissues. Myoglobin (Mb) and hemoglobin (Hb) have been studied for over a century and possibly are the most thoroughly investigated proteins; in fact, every biochemistry textbook devotes a chapter or two to the structure function and evolution of these paradigmatic proteins. It was therefore a great surprise when Thorsten Burmester et al. (1)
discovered a globin expressed in the brain of humans (and mice), appropriately named neuroglobin (Ngb).
Analysis of complementary DNAs (expressed sequence tags) revealed partial globin sequences; these were used to clone and sequence the coding regions, to express the protein (151 aa), and to show that indeed it contains heme and binds O2 reversibly (p
2 torr). Despite the very limited amino acid sequence similarity with Mb and Hb (1)
, Ngb clearly belongs to the superfamily of globin. Determination of the three-dimensional (3D) structure of ferric (or met) human Ngb (2)
, and subsequently of murine Ngb (3)
, unveiled the classical globin fold, albeit endowed with some peculiar features of great significance. Analysis of the Ngb gene showed the presence of three introns instead of two, as customary for all vertebrate hemoglobins. The presence of an additional intron, first reported for leg-hemoglobin (4)
, had been predicted by Go (5)
from a structural analysis of the globin fold. Since Ngb is expressed also in the brain of fishes, amphibians, and birds (6)
, it is likely to be present in the nervous system of all vertebrates. Evolutionary analysis (1)
indicated that the lineage leading to neuroglobins must be older than 550 million years, which is the time calculated to correspond to the separation of hemoglobins and myoglobins in vertebrates (7)
.
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Tissue-specific expression of Ngb
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Ngb is expressed predominantly in the central and peripheral nervous system, but it is also present in the endocrine system (such as the pituitary and adrenal glands, the testis, and the pancreas). Calculations show that average Ngb concentration in the brain is fairly low (0.01% of total protein content or 1 µM), thus apparently inadequate to fullfill the role of an O2 carrier typical of Mb, the concentration of which in the red muscles ranges from 100 to 400 µM (8)
. It is interesting, however, that a much higher concentration of Ngb (100 µM) was found in the neurons of the mammalian retina (whereas it is absent in the retinal pigment epithelium; ref. 9
); here a role in O2 delivery to mitochondria is likely.
It seems undisputed that Ngb is present in brain neurons but absent from glia cells (10
, 11)
. The problem of distribution of Ngb in the mouse brain, attacked by in situ hybridization experiments, is still a matter of debate. In the study reporting the discovery of Ngb, Burmester et al. (1)
found that expression, although present more-or-less throughout, is not uniform. Using a specific polyclonal antibody (pAb; against a synthetic Ngb peptide), Wystub et al. (11)
reported expression of the protein in many brain sites including the cerebral cortex, thalamus, and hypothalamus and nuclei of cranial nerves in the brainstem and the cerebellum; although the data indicated a widespread distribution of Ngb, there are clear differences in the intensity of immunostaining. On the other hand, Mammen et al. (12)
using a radioactive mRNA probe observed a pattern of spatial expression with predominant (if not exclusive) localization in focal regions of the adult murine brain (Fig. 1
A, B). Microscopic examination showed that the probe is localized in the neuronal cell bodies; this finding was consistent with the observation by Sun et al. (13)
that Ngb is present in the cytoplasm of cultured cortical neurons (as found by immunofluorescence).
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Figure 1. Neuroglobin’s expression in the brain and neuroprotective effect in the stroke. A, B) In situ mRNA hybridization reveals that neuroglobin expression in the adult mouse brain is preferential in focal regions (the clear areas seen in these transversal sections). A) forebrain; B) diencephelon. Arc: arcuate nucleus; BLP: basolateral nucleus; BMA: basomedial amigdala; BSTL: bed nucleus of the stria terminalis; LSD, LSV, LSI: lateral septal nuclei; MnPO: median preoptic nucleus; PAG: periaqueductal gray; PH: posterior hypothal area. From Mammen et al. (2002), modified. C–F) Intracerebral overexpression of neuroglobin (with an adeno-associated virus vector) reduces ischemic cerebral injury in the rat; infarct size is indicated as outlined areas. C) Control vector-treated and D) AAV-Ngb-treated. In AAV-Ngb-treated animals the infarct volume (mm3) is reduced (E) and the neurological deficit is improved (F) (from ref. 16
, modified).
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Whether expression of Ngb in the brain is predominantly focal or more widely distributed (though at clearly variable levels) remains to be settled; however, if focal expression was confirmed, it will be a challenge to attempt a correlation between the presence of Ngb in some nuclei and specific neurophysiological effects. Interestingly, Mammen et al. (12)
pointed out that Ngb transcript is clearly detected in areas known to express high concentrations of NOS (nNOS), such as the lateral hypothalamus and the NTS (14)
. These loci are associated with limbic functions and adaptation to stress, which suggested that Ngb is expressed in areas involved in adaptive responses.
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Hypoxic stress responses
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Since Ngb is a bona-fide O2 carrier monomeric hemeprotein, the problem of its role (if any) in the pathophysiology of the nervous system is of primary interest. David Greenberg and colleagues (13
, 16)
have convincingly shown that Ngb is involved in neuronal responses to anoxia or ischemia. Using cerebral cortical neurons, Sun et al. (13)
demonstrated that if cultures were deprived of O2 (for up to 24 h) and then reoxygenated, expression of Ngb and its mRNA were both increased (>2-fold). The mechanism involved is presumably a transcriptional induction via the hypoxia-inducible pathway (such as the hypoxia inducible factor 1), since similar effects were obtained by addition of CoCl2 or deferoxamine. Soon afterward Zhu et al. (15)
showed that also hemin can enhance Ngb expression in several cell types. The effect of hypoxia in enhancing expression, however, was not confirmed by Mammen et al. (12)
using in situ hybridization with a mRNA radioactive probe; no evidence was found for an expanded Ngb expression in focal regions of the brain of adult mice as a result of exposure to a chronic (up to 2 wk) hypoxia (10% O2/90% N2). Taken at face value, these apparently contrasting results suggest that the level of response to the hypoxia/anoxia-reperfusion cycle may depend on the level of O2 deprivation and/or on the acute character of the hypoxic stress. Remarkably, Sun et al. (13)
also showed that reducing Ngb expression (by transfection with an antisense) was associated with a reduced viability of the neurons stressed by hypoxia and conversely that an enhanced expression resulted in a protection from ischemic cell death.
Even more exciting was the first demonstration that Ngb has indeed a protective role against damage due to cerebral ischemia in vivo. Using occlusion (and reperfusion) of the middle cerebral artery in the rat as a model for stroke, Sun et al. (16)
paved the way to possible novel therapeutic approaches of this serious pathology of the humans. The effect of overexpressing Ngb in reducing ischemic cerebral injury may be seen in Fig. 1, C-F
, and vice versa the tissue damage and extent of functional deficit were worsened by reducing Ngb expression. It is of interest that these positive effects of Nbg were attributed largely to survival and/or recovery of the tissue in the so-called penumbral area around the occluded vessel. This is a zone where O2 concentration is obviously very low albeit not zero, while presumably NO concentration is higher than physiological, which (as discussed below) may be of some relevance for a possible mechanism whereby Ngb is involved in neuroprotection.
The O2 affinity of Ngb (p 2 torr; ref 1
; see also ref 17
and ref. therein), and its localization in the cytoplasm led naturally to assumption that its physiological role is O2 supply. Mb is generally considered an O2-reservoir, although the total amount of O2 stored in MbO2 may be sufficient to sustain heart’s respiration for 1 s and probably is used in between beats. The other function of Mb (8)
is to facilitate intracellular O2 diffusion to mitochondria; since the physical mechanism is based on translational diffusion, to make a significant contribution intracellular concentration of Mb must be high enough to compensate for the (20-fold) lower diffusion coefficient of the protein compared with the gas. Since the average concentration of Ngb in the brain (1 µM) is 100 to 400-fold lower that that of Mb in the red muscles, a primary physiological role related to O2 transport is unlikely. In summary, the role of Ngb in the pathophysiology of the brain most probably is not O2 supply but more is likely related to its role in scavenging NO, as proposed also for Mb a few years ago (18
, 19)
.
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Structure and ligand binding
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The 3D structure of Ngb was solved by Pesce et al. (2)
for the human protein and by Vallone et al. (3)
for the murine protein, both in the ferric (or met) state that is unable to bind O2. Ngb has the typical globin fold (Fig. 2
) despite the very limited (20–25%) similarity in amino acid sequence when compared with vertebrate Mb and Hb (1)
. However, Ngb proved to be endowed with some peculiar and unique features, as follows.
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Figure 2. 3D structure of NgbCO and unligated met-Ngb from mouse (from Vallone et al. [28
]). Top) Distal histidine (HisE7), proximal histidine (HisF8), PheCD4, heme group, and loops EF and FG are highlighted. NgbCO in red and unliganded met-Ngb in magenta. Middle) Internal cavities in NgbCO (blue) and unligated met-Ngb (yellow) as determined using SURFNET. The position of Ser-55 is highlighted in green. Bottom) Zoom of active site of NgbCO (red) and unliganded met-Ngb (blue) shows that on CO ligation, the coordination bond with HisE7 (above the heme plane) is broken but imidazole ring moves only slightly, whereas heme tilts and slides toward the right in a preexisting cavity. This conformational change is associated to 1) a substantial change in the position of the proximal HisF8 (seen at bottom) and 2) the obliteration of the proximal branch of the large cavity (highlighted in blue in met-Ngb) and its extension on distal side (indicated with orange contour in NgbCO).
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First of all, the heme iron is hexacoordinate, with the proximal HisF8 and the distal HisE7 providing the two axial coordination bonds (distances 2.1 Å; Fig. 2
); thereby the metal is approximately in the plane of the prophyrin ring. The bond with HisE7 tends to force the E-helix toward the distal heme site, which is crowded by neighboring apolar residues (ValE11, PheCD1, and PheB10). The two axial coordination bonds are present not only in the ferric but also in the ferrous state of Ngb as already shown by optical and Resonance Raman spectroscopy (20
, 21)
. Therefore, binding of an external ligand (O2, CO, NO, or others such as cyanide for metNgb) demands the rupture of the distal bond with HisE7 (ref. 20
21
22
23
and ref. therein). The minimum scheme to describe binding of O2 (or other external ligands) is therefore as follows:
which highlights the need for dissociation of the endogenous HisE7 ligand (A
B) to allow for O2(=L) binding. In principle this step may be quite slow, and in fact when reduced Ngb (species A) is mixed with an excess of L, the rate of complex formation is ligand-concentration independent and limited at 1–2 s half time. Albeit fairly slow, the rate-limiting dissociation of HisE7 (A
B) in reduced Ngb is surprisingly rapid compared with other hexacoordinate reduced hemeproteins (e.g., reduced horse heart cytochrome c). The kinetics of ligand rebinding after flash photolysis of species C has been extensively investigated by time resolved laser spectroscopy (optical and IR; refs. 20
, 22
, 24
, 25
). These sophisticated experiments have led to a fairly complete understanding of the competing reactions between the internal and external coordination of a ligand on the distal side. It has been demonstrated that the bimolecular rebinding rate constant is fairly high for all the gaseous ligands (between 4 and 15x107 M–1·s–1). Analysis of the kinetic data allowed to rationalize the fairly "normal" O2 affinity of Ngb vis-a-vis the low dissociation rate constant (k off=0.8 s–1) on the basis of the competition with HisE7 (26)
.
The second outstanding feature in the structure of Ngb is the presence of a huge internal cavity (Fig. 2)
, which connects the heme distal and proximal sides and is in contact with the bulk through a channel flanked by TyrF3 (2
, 3)
. The volume of this tunnel (almost 300 Å3; ref. 3
) and its highly hydrophobic character are quite peculiar; on the distal side, it is connected with a couple of smaller cavities, one topologically corresponding to the so-called Xe4 cavity seen in sperm whale Mb (27)
. The "external" wall of this cavity is constituted by the EF corner, which was found to be characterized by an unusual mobility (in between residues 77 and 85) just like the CD corner (see ref. 3
).
Determination of the 3D structure of NgbCO was revealing (28)
. The most unexpected finding was the magnitude of the conformational change associated to binding of CO, which demands the rupture of the distal HisE7-iron bond. In NgbCO, HisE7 stays (almost) put and binding of the gas is associated to a large sliding motion of the heme toward the interior and an extensive reorganization of the internal cavity (see Fig. 2
). The total volume of the tunnel is almost unchanged, but while its distal branch extends toward the surface, the proximal one is obliterated by the heme in its new position. Thus one may venture to propose that a role for the huge internal cavity may be to yield space for the heme, thereby facilitating the sliding motion linked to CO binding and the coupled structural changes (such as the change in external mobility of loops and control of access to the tunnel). Is such an unexpected conformational change related to the neuroprotective role of Ngb against hypoxia?
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A sensor for signal transduction?
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Since the mechanism whereby Ngb exerts its function is still a conundrum, it may be worthwhile to summarize briefly some theoretical possibilities. We have already outlined above why the most obvious option, i.e., an O2 carrier just like Mb, is hardly defendable; although Ngb’s binding and rate constants for O2 are in the correct ballpark for the job, its concentration is much too low. Other functions that have been often discussed (see also ref. 6
) are 1) to be involved in NO detoxification by catalyzing reduction of 2NO to N2O (NO reductase activity), which has been tested in vitro with negative results; or 2) to be endowed in an O2-oxidoreductase activity, which is not supported by polarographic experiments (13
, 29)
.
A new vista that, albeit still questionable, is very interesting envisages that Ngb is a redox-coupled sensor regulating a G-protein coupled transduction pathway. The group led by Isao Morishima (30)
discovered that ferric human Ngb binds to the GDP-bound state of the subunit of the heterotrimeric (Gß) G-protein, and thus acts as a guanine-nucleotide dissociation inhibitor (GDI); the GDP/GTP exchange process, which is vital for reassociation of G to the Gß, is inhibited in the met-Ngb/G[GDP] complex. This liberates the Gß and thereby activates the coupled signal transduction pathway, which is protective toward oxidative stress (31)
. The additional interesting findings were 1) that Ngb-CO is inactive as a GDI in the in vitro assay and thus the sensor efficacy depends on the redox/ligation state (30)
; and 2) that the GDI activity of met-Ngb can be modulated or even abolished by some site-directed mutations (32)
, particularly of Glu53 in the CD-D region (but also Arg97, Glu118, and Glu151).
The original inspiration for such an experiment, which was based on an alleged homology of the Ngb sequence with that of regulators of G-protein signaling and the corresponding domains of G-protein coupled receptor kinases, has been questioned (6)
. Moreover, met-Ngb from zebrafish is devoid of GDI activity (32)
, which may cast some doubts on the generality of this role in signaling. Nevertheless, it is intriguing that formation of a complex between G and Ngb depends on the oxidation/ligation state of the hemeprotein and thus may be correlated to the substantial conformational changes observed (28)
in comparing the structure of met-Ngb and NgbCO, i.e., the ligand-linked heme sliding, the change in the topology of the big tunnel, and the reduction in the mobility of external loops (the EF and the CD corners).
Based on this overall scenario, Brunori et al. (29)
proposed that Ngb may be a sensor of the relative concentration of O2 and NO in the tissue. By rapid mixing experiments, they proved that NgbO2 and NO react very rapidly (k>107 M–1·s–1 at 5°C) with formation of nitrate, via a peroxinitrite (ONOO–)–Fe(III) bound intermediate, which mimics the same reaction studied in Mb and Hb (33
, 34)
. Brunori et al. (29)
presented a branched scheme (reproduced in Fig. 3
) which may acquire significance when [O2] tends to be lower and [NO] higher than physiological. The underlying assumption is that ferrous Ngb bound to O2 or NO would have the same 3D structure observed for NgbCO and thereby would be devoid of GDI activity. The O2-binding pathway in Fig. 3
, with subsequent very rapid oxidation by NO, would have the double effect of competing with the direct formation NgbNO (presumably ineffective as a GDI) and of disposing of NO, which is harmful to cellular respiration (18
, 35
and ref. therein). These conditions may possibly correspond to those prevailing in the so-called penumbral area around an occluded vessel, which is hypoxic and experiencing an overproduction of NO because of induced expression of NO synthases. As shown by David Greenberg and colleagues (16)
, it is in the penumbral area that the level of expression of Ngb makes a dramatic difference in the level of neuroprotection. Moreover (as outlined above), it is intriguing that Ngb is detected in areas of the brain that are known to express higher concentrations of NOS (12
, 14)
. In this scenario, the possibility that Ngb may also play a role in the degradation and quenching of reactive oxygen species should not be overlooked given that harmful effects of hypoxia on viability of the neuron’ have been observed after reperfusion of a tissue subject to what Salvador Moncada calls NO hypoxia (due to inhibition of cytochrome-c-oxidase by NO, see ref 18
, 35
). In any case, these possible functions of Ngb demand the demonstration that the brain expresses a significant met-Ngb reductase activity, which is necessary to restore the reduced state competent in O2 binding. More work ahead is demanded for, but more exciting results are expected.
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ACKNOWLEDGMENTS
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This work was partially supported by MIUR of Italy (PRIN 2005 to M. Brunori). The authors thank Dr. Stefania Contardi for assistance in the preparation of this paper.
Received for publication June 8, 2006.
Accepted for publication June 23, 2006.
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REFERENCES
|
|---|
- Burmester, T., Weich, B., Reinhardt, S., Hankeln, T. (2000) A vertebrate globin expressed in the brain. Nature 407,520-523[CrossRef][Medline]
- Pesce, A., Dewilde, S., Nardini, M., Moens, L., Ascenzi, P., Hankeln, T., Burmester, T., Bolognesi, M. (2003) Human brain neuroglobin structure reveals a distinct mode of controlling oxygen affinity. Structure 11,1087-1095[Medline]
- Vallone, B., Nienhaus, K., Brunori, M., Nienhaus, G. U. (2004) The structure of murine neuroglobin: Novel pathways for ligand migration and binding. Proteins 56,85-92[CrossRef][Medline]
- Jensen, E. O., Paludan, K., Hyldignielsen, J. J., Jorgensen, P., Marcker, K. A. (1981) The structure of a chromosomal leghaemoglobin gene from soybean. Nature 291,677-679[CrossRef]
- Go, M. (1981) Correlation of DNA exonic regions with protein structural units in haemoglobin. Nature 291,90-92[CrossRef][Medline]
- Burmester, T., Hankeln, T. (2004) Neuroglobin: A Respiratory Protein of the Nervous System. News Physiol. Sci. 19,110-113[Abstract/Free Full Text]
- Goodman, M., Moore, G. W., Matsuda, G. (1975) Darwinian evolution in the genealogy of haemoglobin. Nature 253,603-608[CrossRef][Medline]
- Wittenberg, B. A., Wittenberg, J. B. (1989) Transport of oxygen in muscle. Annu. Rev. Physiol. 51,857-878[CrossRef][Medline]
- Schmidt, M., Giessl, A., Laufs, T., Hankeln, T., Wolfrum, U., Burmester, T. (2003) How does the eye breathe? Evidence for neuroglobin-mediated oxygen supply of the mammalian retina. J. Biol. Chem. 278,1932-1935[Abstract/Free Full Text]
- Reuss, S., Saaler-Reinhardt, S., Weich, B., Wystub, S., Reuss, M., Burmester, T., Hankeln, T. (2002) Expression analysis of neuroglobin mRNA in rodent tissues. Neuroscience 115,645-656[CrossRef][Medline]
- Wystub, S., Laufs, T., Schmidt, M., Burmester, T., Maas, U., Saaler-Reinhardt, S., Hankeln, T., Reuss, S. (2003) Localisation of neuroglobin protein in the mouse brain. Neurosci. Lett. 346,114-116[CrossRef][Medline]
- Mammen, P. P. A., Shelton, J. M., Goetsch, S. C., Williams, S. C., Richardson, J. A., Garry, M. G., Garry, D. J. (2002) Neuroglobin, a novel member of the globin family, is expressed in focal regions of the brain. J. Histochem. Cytochem. 50,1591-1598[Abstract/Free Full Text]
- Sun, Y., Jin, K., Mao, X. O., Zhu, Y., Greenberg, D. A. (2001) Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury. Proc. Natl. Acad. Sci. U. S. A. 98,15306-15311[Abstract/Free Full Text]
- Vincent, S. R., Kimura, H. (1992) Histochemical mapping of nitric-oxide synthase in the rat-brain. Neuroscience 46,755-784[CrossRef][Medline]
- Zhu, Y., Sun, Y., Jin, K., Greenberg, D. A. (2002) Hemin induces neuroglobin expression in neural cells. Blood 100,2494-2498[Abstract/Free Full Text]
- Sun, Y., Jin, K., Peel, A., Mao, X. O., Xie, L., Greenberg, D. A. (2003) Neuroglobin protects the brain from experimental stroke in vivo. Proc. Natl. Acad. Sci. U. S. A. 100,3497-3500[Abstract/Free Full Text]
- Uzan, J., Dewilde, S., Burmester, T., Hankeln, T., Moens, L., Hamdane, D., Marden, M. C., Kiger, L. (2004) Neuroglobin and other hexacoordinated hemoglobins show a weak temperature dependence of oxygen binding. Biophys. J. 87,1196-1204[CrossRef][Medline]
- Brunori, M. (2001) Nitric oxide, cytochrome-c oxidase and myoglobin. Trends Biochem. Sci. 26,21-23[CrossRef][Medline]
- Floegel, U., Merx, M. W., Goedecke, A., Decking, U. K., Schrader, J. (2001) Myoglobin: A scavenger of bioactive NO. Proc. Natl. Acad. Sci. U. S. A. 98,735-740[Abstract/Free Full Text]
- Trent, J. T., III, Watts, R. A., Hargrove, M. S. (2001) Human neuroglobin, a hexacoordinate hemoglobin that reversibly binds oxygen. J. Biol. Chem. 276,30106-30110[Abstract/Free Full Text]
- Couture, M., Burmester, T., Hankeln, T., Rousseau, D. L. (2001) The heme environment of mouse neuroglobin. Evidence for the presence of two conformations of the heme pocket. J. Biol. Chem. 276,36377-36382[Abstract/Free Full Text]
- Dewilde, S., Kiger, L., Burmester, T., Hankeln, T., Baudin-Creuza, V., Aerts, T., Marden, M. C., Caubergs, R., Moens, L. (2001) Biochemical characterization and ligand binding properties of neuroglobin, a novel member of the Globin Family J. Biol. Chem. 276,38949-38955
- Ascenzi, P., Bocedi, A., deSanctis, D., Pesce, A., Bolognesi, M., Marden, M. C., Dewilde, S., Moens, L., Hankeln, T., Burmester, T. (2004) Neuroglobin and cytoglobin: Two new entries in the hemoglobin superfamily. Biochem. Mol. Biol. Educ. 32,305-313
- Kriegl, J. M., Bhattacharyya, A. J., Nienhaus, K., Deng, P., Minkow, O., Nienhaus, G. U. (2002) Ligand binding and protein dynamics in neuroglobin. Proc. Natl. Acad. Sci. U. S. A. 99,7992-7997[Abstract/Free Full Text]
- Van Doorslaer, S., Dewilde, S., Kiger, L., Nistor, S. V., Goovaerts, E., Marden, M. C., Moens, L. (2003) Nitric oxide binding properties of neuroglobin. A characterization by EPR and flash photolysis. J. Biol. Chem. 278,4919-4925[Abstract/Free Full Text]
- Hamdane, D., Kiger, L., Dewilde, S., Green, B. N., Pesce, A., Uzan, J., Burmester, T., Hankeln, T., Bolognesi, M., Moens, L., et al (2003) The redox state of the cell regulates the ligand binding affinity of human neuroglobin and cytoglobin. J. Biol. Chem. 278,51713-51721[Abstract/Free Full Text]
- Tilton, R. F., Jr, Kuntz, I. D., Jr, Petsko, G. A. (1984) Cavities in proteins: structure of a metmyoglobin-xenon complex solved to 1.9 Å. Biochemistry 23,2849-2857[CrossRef][Medline]
- Vallone, B., Nienhaus, K., Matthes, A., Brunori, M., Nienhaus, G. U. (2004) The structure of carbonmonoxy neuroglobin reveals a heme-sliding mechanism for control of ligand affinity Proc. Natl. Acad. Sci. U. S. A. 101,17351-17356[Abstract/Free Full Text]
- Brunori, M., Giuffrè, A., Nienhaus, K., Nienhaus, G. U., Scandurra, F. M., Vallone, B. (2005) Neuroglobin, nitric oxide, and oxygen: functional pathways and conformational changes. Proc. Natl. Acad. Sci. U. S. A. 102,8483-8488[Abstract/Free Full Text]
- Wakasugi, K., Nakano, T., Morishima, I. (2003) Oxidized human neuroglobin acts as a heterotrimeric G protein guanine nucleotide dissociation inhibitor. J. Biol. Chem. 278,36505-36512[Abstract/Free Full Text]
- Schwindinger, W. F., Robishaw, J. D. (2001) Heterotrimeric G-protein ß-dimers in growth and differentiation. Oncogene 20,1653-1660[CrossRef][Medline]
- Wakasugi, K., Morishima, I. (2005) Identification of residues in human neuroglobin crucial for guanine nucleotide dissociation inhibitor activity. Biochemistry 44,2943-2948[CrossRef][Medline]
- Eich, R. F., Li, T., Lemon, D. D., Doherty, D. H., Curry, S. R., Aitken, J. F., Mathews, A. J., Johnson, K. A., Smith, R. D., Phillips, G. N., Jr, Olson, J. S. (1996) Mechanism of NO-induced oxidation of myoglobin and hemoglobin. Biochemistry 35,6976-6983[CrossRef][Medline]
- Herold, S., Exner, M., Nauser, T. (2001) Kinetic and mechanistic studies of the NO-mediated oxidation of oxymyoglobin and oxyhemoglobin. Biochemistry 40,3385-3395[CrossRef][Medline]
- Moncada, S., Erusalimsky, J. D. (2002) Does nitric oxide modulate mitochondrial energy generation and apoptosis?. Nat. Rev. Mol. Cell. Biol. 3,214-220[CrossRef][Medline]
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TOP
ABSTRACT
INTRODUCTION
