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 O₂, regulating taxis away or towards high O₂ 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.

Keywords: Cancer; Hemoglobin; Hypoxia; Myoglobin; Nitric oxide; Oxidative stress.

Fig. 1

The three globin families. The F (Flavo) family, the S (Sensor) family and the T (Truncated) family can all be found in a chimeric or in a single domain configuration. T globins may further display multi-unit assemblies. Chimeric (FHb) and single-domain (Fgb) F globins are found in bacteria and eukaryotes, but absent in archaea, and are numerically preponderant. S family globins include chimeric globin-coupled sensor proteins (GCS) which carry a C-terminal output domain (including HemAT for aerotactic heme sensor), and sensor single domain globins (SSDgb) and their shorter version the protoglobins (Pgb). HemAT is found in bacteria and archaea, SSDgbs are found in bacteria and eukaryotes, and Pgb in bacteria and archaea. T family globins exist in three structural subfamilies, T1, T2 and T3, which, in bacteria, are also termed N, O and P, respectively. Chimeric and multi-unit T globins can be found in bacteria (T2/O and T3/P) and eukaryotes (T1), whereas single domain T globins appear in bacteria (T1/N, T2/O and T3/P), in archaea (T1/N) and eukaryotes (T1 and T2).

Fig. 2

Vertebrate globins and their distribution. Schematic cladogram of the vertebrate globin repertoire. Notable differences in expression patterns are summarized on the right of each phylogenetic branch, including the selective loss of Hb and Mb in ray-finned fish subspecies or the selective duplication of Mb in ray-finned fish subspecies, and the duplications of Mb and GbE in lungfishes. Hb: hemoglobin, Mb: myoglobin, Ngb: neuroglobin, Cygb: cytoglobin, Adgb: androglobin, GbE: globin E, GbX: globin X, GbY: globin Y.

Fig. 3

Human globin expression atlas. (A) Schematic representation of globin expression sites within the human body. (B) RNA-sequencing-based mRNA expression in TPM (transcripts per million) of Hb, Mb, Ngb, Cygb and Adgb within tissues from healthy donors. The dataset was generated and adapted from the Genotype-Tissue Expression (GTEx) project (https://www.gtexportal.org.com). Hb: hemoglobin, Mb: myoglobin, Ngb: neuroglobin, Cygb: cytoglobin, Adgb: androglobin.