Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

Abstract

Vertebrate hemoglobin (Hb) and myoglobin (Mb) were among the first proteins whose structures and sequences were determined over 50 years ago. In the subsequent pregenomic period, numerous related proteins came to light in plants, invertebrates and bacteria, that shared the myoglobin fold, a signature sequence motif characteristic of a 3-on-3 α-helical sandwich. Concomitantly, eukaryote and bacterial globins with a truncated 2-on-2 α-helical fold were discovered. Genomic information over the last 20 years has dramatically expanded the list of known globins, demonstrating their existence in a limited number of archaeal genomes, a majority of bacterial genomes and an overwhelming majority of eukaryote genomes. In vertebrates, 6 additional globin types were identified, namely neuroglobin (Ngb), cytoglobin (Cygb), globin E (GbE), globin X (GbX), globin Y (GbY) and androglobin (Adgb). Furthermore, functions beyond the familiar oxygen transport and storage have been discovered within the vertebrate globin family, including NO metabolism, peroxidase activity, scavenging of free radicals, and signaling functions. The extension of the knowledge on globin functions suggests that the original roles of bacterial globins must have been enzymatic, involved in defense against NO toxicity, and perhaps also as sensors of O 2 , regulating taxis away or towards high O 2 concentrations. In this review, we aimed to discuss the evolution and remarkable functional diversity of vertebrate globins with particular focus on the variety of non-canonical expression sites of mammalian globins and their according impressive variability of atypical functions.

Androglobin gene expression patterns and FOXJ1-dependent regulation indicate its functional association with ciliogenesis

“…Genomic analyses have considerably altered and extended our view of the globin family in mammals, leading to the discovery of novel globin types such as neuroglobin (NGB) and cytoglobin (CYGB), which are expressed in nerve and fibroblast-like cells, respectively ( 1 , 2 ). Both globin types perform yet-to-be-illuminated functions, which possibly reside in antioxidant defense, reactive oxygen species signaling, or even lipid metabolism ( 3 , 4 ).…”

Whole genome duplications and the diversification of the Globin-X genes of vertebrates

“…Since the time of its initial discovery (Roesner et al, 2005), GbX went from being an obscure gene found in a very limited sample of vertebrates to becoming a credible candidate to provide clues about the functional role of the ancestor of all animal globins (Blank et al, 2011; Song et al, 2020). This change in paradigm came with an increased interest in deciphering its evolutionary history and its still elusive functional role (Burmester and Hankeln, 2014; Keppner et al, 2020). We have recently documented the presence of GbX paralogs in arthropods (Prothmann et al, 2020), confirming phylogenetic predictions that indicate that the origin of GbX predates the split between deuterostomes and protostomes (Burmester et al, 2002; Roesner et al, 2005; Dröge and Makałowski, 2011; Blank and Burmester, 2012; Hoffmann et al, 2012a)(Opazo et al, 2015), which is estimated to have occurred ~ 730 million years ago (Kumar et al, 2017).…”

“…Globins are small, oxygen-binding hemoproteins found in all domains of life (Vinogradov et al, 2005). The globin superfamily of vertebrates provides an excellent example of how the interplay between local gene duplications, whole-genome duplications, amino acid and regulatory changes can fuel the evolution of novel protein functions (Storz et al, 2011, 2013; Keppner et al, 2020). The different types of globins in vertebrate genomes can be classified into four groups 1)-androglobin, 2)-neuroglobin,3) globin-X (GbX), and 4)-vertebrate-specific globins.…”

“…Androglobin, the most recently discovered member of the vertebrate globins, is a chimeric protein that includes a rearranged globin domain that can be traced back to the common ancestor of choanoflagellates and animals (Hoogewijs et al, 2012). Neuroglobin also represents an ancient globin lineage that originated prior to the split between protostomes and deuterostomes (Burmester et al, 2000(Burmester et al, , 2002Roesner et al, 2005;Dröge and Makałowski, 2011;Blank and Burmester, 2012;Hoffmann et al, 2012a), and in spite of intensive efforts, its physiological function remains a mystery (Fago et al, 2004;Ascenzi et al, 2014;Burmester and Hankeln, 2014;Keppner et al, 2020).…”

Androglobin, a chimeric mammalian globin, is required for male fertility

“…Globins are small globular metallo-proteins, which have the capacity to reversibly bind gaseous ligands via a typical 8 alpha-helical structure in which a heme prosthetic group can be embedded. In mammals, five globin types exist: the well-established hemoglobin (Hb) and myoglobin (Mb), neuroglobin (Ngb) in neuronal cells, cytoglobin (Cygb) ubiquitously expressed in fibroblasts, and the more recently identified androglobin (Adgb), predominantly expressed in mammalian testis tissue (Keppner et al 2020).…”