Neuroglobin and cytoglobin. Fresh blood for the vertebrate globin family

Abstract

Neuroglobin and cytoglobin are two recently discovered members of the vertebrate globin family. Both are intracellular proteins endowed with hexacoordinated heme-Fe atoms, in their ferrous and ferric forms, and display O2 affinities comparable with that of myoglobin. Neuroglobin, which is predominantly expressed in nerve cells, is thought to protect neurons from hypoxic-ischemic injury. It is of ancient evolutionary origin, and is homologous to nerve globins of invertebrates. Cytoglobin is expressed in many different tissues, although at varying levels. It shares common ancestry with myoglobin, and can be traced to early vertebrate evolution. The physiological roles of neuroglobin and cytoglobin are not completely understood. Although supplying cells with O2 is the likely function, it is also possible that both globins act as O2-consuming enzymes or as O2 sensors. Here, we review what is currently known about neuroglobin and cytoglobin in terms of their function, tissue distribution and relatedness to the well-known hemoglobin and myoglobin. Strikingly, the data reveal that O2 metabolism in cells is more complicated than was thought before, requiring unexpected O2-binding proteins with potentially novel functional features.

Figure 1

The classical globin fold. (A) A ribbon view of the typical mammalian globin fold: the 'three-over-three' α-helical sandwich is highlighted in two colours and the helices are labelled according to the conventional globin nomenclature (A, B, C.....H, starting from the N-terminus). Within each helix (as defined in sperm whale Mb, the prototype monomeric globin structure shown in the figure) residues are assigned sequential numbering. Thus, residue E7 occupies the seventh position within the E helix of the reference globin fold. To avoid discrepancies related to different protein lengths, globin amino acid sequences and structures are compared using such defined topological sites as reference (Perutz, 1979; Kapp et al., 1995). (B) A view of the heme proximal and distal sites, defined by E- and F-helices, together with the key residues PheCD1, HisE7 and HisF8 and the heme O₂ ligand. The Fe coordination bonds with the proximal HisF8 residue and the O₂ ligand are indicated by red dashed lines, while the hydrogen bond between O₂ and the distal HisE7 residue is indicated in blue. Both figures are drawn with MOLSCRIPT (Kraulis, 1991).

Figure 2

Multiple amino acid sequence alignment of human Mb, Hb (α and β chains), Ngb and Cygb. The stretch of sequence encoding α-helices and the globin topological numbering (referred to human Mb) are shown above the sequence. Key distal sites and heme binding residues are highlighted in yellow, and structurally relevant residues are marked in blue. The asterisks identify residues in contact with the heme in human Mb. Residue numbering refers to human Cygb. The intron positions are marked by arrows, and labeled below the aligned sequences.

Figure 3

An evolutionary model of human globins. The different locations of globin genes in human chromosomes are reported at the top of the figure, distinguishing between the functional genes (in color) and the pseudogenes (in grey). Figure modified from Burmester et al. (2002).