Neuroglobin and cytoglobin in search of their role in the vertebrate globin family

doi:10.1016/j.jinorgbio.2004.11.009

Journal of Inorganic Biochemistry

Volume 99, Issue 1, January 2005, Pages 110-119

https://doi.org/10.1016/j.jinorgbio.2004.11.009 Get rights and content

Abstract

Neuroglobin and cytoglobin are two recent additions to the family of heme-containing respiratory proteins of man and other vertebrates. Here, we review the present state of knowledge of the structures, ligand binding kinetics, evolution and expression patterns of these two proteins. These data provide a first glimpse into the possible physiological roles of these globins in the animal’s metabolism. Both, neuroglobin and cytoglobin are structurally similar to myoglobin, although they contain distinct cavities that may be instrumental in ligand binding. Kinetic and structural studies show that neuroglobin and cytoglobin belong to the class of hexa-coordinated globins with a biphasic ligand-binding kinetics. Nevertheless, their oxygen affinities resemble that of myoglobin. While neuroglobin is evolutionarily related to the invertebrate nerve-globins, cytoglobin shares a more recent common ancestry with myoglobin. Neuroglobin expression is confined mainly to brain and a few other tissues, with the highest expression observed in the retina. Present evidence points to an important role of neuroglobin in neuronal oxygen homeostasis and hypoxia protection, though other functions are still conceivable. Cytoglobin is predominantly expressed in fibroblasts and related cell types, but also in distinct nerve cell populations. Much less is known about its function, although in fibroblasts it might be involved in collagen synthesis.

Section snippets

Globins: vertebrate novices add complexity to the family

Globins are small globular metalloproteins typically consisting of about 150 amino acids and comprising eight α-helical segments (named A-H) that display a characteristical 3-over-3 α-helical sandwich structure. This conserved ‘globin fold’ identifies them as members of the globin protein superfamily [1], [2], [3], which also comprises truncated versions whose globin fold consists of only four α-helices [4]. Globins contain a heme prosthetic group (Fe-protoporphyrin IX), by which they can

Protein structure and ligand binding

Ngb is a substantially divergent member of the globin family, displaying only 20–25% amino acid sequence identity to Mbs and Hbs [13, Fig. 2]. Ngb represents a typical Mb-type monomeric globin, which can bind O₂ reversibly [13], [17], [18]. In spite of its sequence differences, Ngb features the conserved globin fold consisting of the eight α-helices A-H, albeit with some peculiarities which reflect a pronounced adaptive potential of this basic globin structure (Fig. 3). The crystal structure of

Protein structure and ligand binding

Cygb shares about 30% amino acid sequence identity with Mb, pointing at a shared evolutionary ancestry [14], [15], [16]. Compared to Mb, mammalian Cygb is unusually long, containing 190 amino acids owing to extensions of about 20 amino acids at both, the N- and the C-terminus (Fig. 2). Part of the N-terminal extension may be explained by sequence motif duplication, while the C-terminal extension partly derives from a small additional exon, which has been recruited during mammalian evolution and

Two globins in search of their role in the family (and in the cell)

Theoretically, and partly in analogy to other globins, we can consider several possible cellular functions for Ngb and Cygb (Fig. 4) and discuss them in light of the currently available data:

(a)
As with Mb and many other Mb-type molecules, both novel globins could either store O₂ or assist in the diffusion of O₂ within the cell towards the mitochondria [7].
(b)
Both globins could function as oxygen sensor proteins, which have been well-studied in bacteria [55]. Alternatively, they could be involved in

Note added in proof

Recent papers describe the structures of mouse bis-histidyl ferric and CO-bound ferrous mouse Ngb (Vallone et al. (2004) Proteins 56, 85–92; Vallone et al. (2004) PNAS, e-publication), and of human wildtype CYGB (Sugimoto et al. (2004) J. Mol. Biol. 339, 873–885). Ligand binding characteristics of NGB and CYGB have been further analyzed (Fago et al. (2004) J. Biol. Chem. 279, 44417–26). Chicken Ngb and Cygb and the fifth vertebrate globin (GbX) are published (Kugelstadt et al. (2004) Biochem.

Acknowledgements

We are very grateful to Jonathan and Beatrice Wittenberg (New York), Rainald Schmidt-Kastner (Miami), Nigel Woolf (San Diego) and Joachim Fandrey (Essen) for discussions. This work was supported by grants from DFG (Ha2103/3 and Bu956/5 to T.H. and T.B.), the Danish Natural Science Research Council (A.F. and R.E.W), the European Union FP5 project (QLG3-CT2002-01548) to M.B., and the EU project ‘Neuroglobin and the survival of the brain’ (QLRT-2001-01548). S.D. is a postdoctoral fellow of the

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Neuroglobin and cytoglobin in search of their role in the vertebrate globin family

Abstract

Section snippets

Globins: vertebrate novices add complexity to the family

Protein structure and ligand binding

Protein structure and ligand binding

Two globins in search of their role in the family (and in the cell)

Note added in proof

Acknowledgements

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