Globin superfamily members share a common three-dimensional fold. This 'globin fold' typically consists of eight alpha helices, although some proteins have additional helix extensions at their termini. Since the globin fold contains only helices, it is classified as an all-alpha protein fold. The globin fold is found in its namesake globin families as well as in phycocyanins. The globin fold was thus the first protein fold discovered.
Helix packing
The eight helices of the globin fold core share significant nonlocal structure, unlike other structural motifs in which amino acids close to each other in primary sequence are also close in space. The helices pack together at an average angle of about 50 degrees, significantly steeper than other helical packings such as the helix bundle. The exact angle of helix packing depends on the sequence of the protein, because packing is mediated by the sterics and hydrophobic interactions of the amino acidside chains near the helix interfaces.
Evolution
Globins evolved from a common ancestor and can be divided into three groups: single-domain globins, and two types of chimeric globins, flavohaemoglobins and globin-coupled sensors. Bacteria have all three types of globins, while archaea lack flavohaemoglobins, and eukaryotes lack globin-coupled sensors. Several functionally different haemoglobins can coexist in the same species. Eight globins are known to occur in vertebrates: androglobin, cytoglobin, globin E, globin X, globin Y, hemoglobin, myoglobin and neuroglobin.
Sequence conservation
Although the fold of the globin superfamily is highly evolutionarily conserved, the sequences that form the fold can have as low as 16% sequence identity. While the sequence specificity of the fold is not stringent, the hydrophobic core of the protein must be maintained and hydrophobic patches on the generally hydrophilic solvent-exposed surface must be avoided in order for the structure to remain stable and soluble. The most famous mutation in the globin fold is a change from glutamate to valine in one chain of the hemoglobin molecule. This mutation creates a "hydrophobic patch" on the protein surface that promotes intermolecular aggregation, the molecular event that gives rise to sickle-cell anemia.
Cytoglobin: an oxygen sensor expressed in multiple tissues. Related to neuroglobin.
Erythrocruorin: highly cooperative extracellular respiratory proteins found in annelids and arthropods that are assembled from as many as 180 subunit into hexagonal bilayers.
Non-symbiotic haemoglobin : occurs in non-leguminous plants, and can be over-expressed in stressed plants.
Flavohaemoglobins : chimeric, with an N-terminal globin domain and a C-terminal ferredoxin reductase-like NAD/FAD-binding domain. FHb provides protection against nitric oxide via its C-terminal domain, which transfers electrons to haem in the globin.
Globin E: a globin responsible for storing and delivering oxygen to the retina in birds
Globin-coupled sensors: chimeric, with an N-terminal myoglobin-like domain and a C-terminal domain that resembles the cytoplasmic signalling domain of bacterial chemoreceptors. They bind oxygen, and act to initiate an aerotactic response or regulategene expression.
Protoglobin: a single domain globin found in archaea that is related to the N-terminal domain of globin-coupled sensors.
Truncated 2/2 globin: lack the first helix, giving them a 2-over-2 instead of the canonical 3-over-3 alpha-helical sandwich fold. Can be divided into three main groups based on structural features.
HbN : a truncated haemoglobin-like protein that binds oxygen cooperatively with a very high affinity and a slow dissociation rate, which may exclude it from oxygen transport. It appears to be involved in bacterial nitric oxide detoxification and in nitrosative stress.
Cyanoglobin : a truncated haemoprotein found in cyanobacteria that has high oxygen affinity, and which appears to serve as part of a terminal oxidase, rather than as a respiratory pigment.
HbO : a truncated haemoglobin-like protein with a lower oxygen affinity than HbN. HbO associates with the bacterial cell membrane, where it significantly increases oxygen uptake over membranes lacking this protein. HbO appears to interact with a terminal oxidase, and could participate in an oxygen/electron-transfer process that facilitates oxygen transfer during aerobic metabolism.
Glb3: a nuclear-encoded truncated haemoglobin from plants that appears more closely related to HbO than HbN. Glb3 from Arabidopsis thaliana exhibits an unusual concentration-independent binding of oxygen and carbon dioxide.
