Pathways & interactions
Globin, extracellular (IPR014610)
Short name: Haemoglobin_extracell
- Globin (IPR000971)
- Globin, extracellular (IPR014610)
Globins are haem-containing proteins involved in binding and/or transporting oxygen. They belong to a very large and well studied family that is widely distributed in many organisms [PMID: 17540514]. Globins have 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 [PMID: 16600051]. Several functionally different haemoglobins can coexist in the same species. The major types of globins include:
- Haemoglobin (Hb): tetramer of two alpha and two beta chains, although embryonic and foetal forms can substitute the alpha or beta chain for ones with higher oxygen affinity, such as gamma, delta, epsilon or zeta chains. Hb transports oxygen from lungs to other tissues in vertebrates [PMID: 16888280]. Hb proteins are also present in unicellular organisms where they act as enzymes or sensors [PMID: 15598493].
- Myoglobin (Mb): monomeric protein responsible for oxygen storage in vertebrate muscle [PMID: 15339940].
- Neuroglobin: a myoglobin-like haemprotein expressed in vertebrate brain and retina, where it is involved in neuroprotection from damage due to hypoxia or ischemia [PMID: 12962627]. Neuroglobin belongs to a branch of the globin family that diverged early in evolution.
- Cytoglobin: an oxygen sensor expressed in multiple tissues. Related to neuroglobin [PMID: 15804833].
- Erythrocruorin: highly cooperative extracellular respiratory proteins found in annelids and arthropods that are assembled from as many as 180 subunit into hexagonal bilayers [PMID: 17084861].
- Leghaemoglobin (legHb or symbiotic Hb): occurs in the root nodules of leguminous plants, where it facilitates the diffusion of oxygen to symbiotic bacteriods in order to promote nitrogen fixation.
- Non-symbiotic haemoglobin (NsHb): occurs in non-leguminous plants, and can be over-expressed in stressed plants [PMID: 17540516].
- Flavohaemoglobins (FHb): 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 [PMID: 11092893].
- 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 regulate gene expression [PMID: 11481493, PMID: 15598488].
- Protoglobin: a single domain globin found in archaea that is related to the N-terminal domain of globin-coupled sensors [PMID: 15096613].
- 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 (I, II and II) based on structural features [PMID: 17701548].
In vertebrates, haemoglobins function to transport oxygen in blood plasma. Hb binds oxygen in the reduced [Fe(II)] state. Hb is composed of four globins in a tetrahedral arrangement, typically two alpha- and two beta-globins, where each monomer binds a haem group. The alpha and beta subunits are highly similar in sequence, but differ structurally in that the beta subunit contains an alpha-helix (the D helix) that is missing in the alpha subunit [PMID: 7599114]. There is at least one haem-site ligand on each of the alpha and beta subunits. The imidazole ring of the 'proximal' His residue provides the fifth haem iron ligand; the other axial haem iron position remains essentially free for oxygen coordination. The binding of oxygen and carbon dioxide is associated with a variation of the haem iron coordination. Oxygen binding results in a transition from high-spin to low-spin iron, with accompanying changes in the Fe-N bond lengths and coordination geometry. In Hb, these subtle changes lead to the well-known cooperative effect of oxygen binding, which involves a relaxed (R) state when oxygen is bound and a tense (T) state upon oxygen release [PMID: 1445857, PMID: 12093902]. The alpha or beta subunits are substituted in embryo and foetal Hb with subunits that have higher oxygen affinity (gamma, delta, epsilon, pi or zeta subunits). There are at least three types of human embryonic Hb (zeta2epsilin2, alpha2epsilon2, zeta2gamma2) and two foetal Hb (alpha2gamma2, alpha2delta2). It has been hypothesised that the embryonic alpha-haemoglobin family diverged considerably earlier than the beta-haemoglobin line, as reflected in the greater diversity found amongst alpha sequences [PMID: 6157691].
This entry represents secreted globins and haemoglobins found primarily in annelid worms [PMID: 11294835, PMID: 17451435]. These proteins are very large, consisting of multiple subunits linked by disulphide bonds [PMID: 16766219]. For example, the extracellular haemoglobin from Lumbricus terrestris (Common earthworm) consists of 12 subunits arranged in a hexagonal bilayer structure, where each of the 12 subunits is itself composed of disulphide-linked trimers (chains A, B, and C) and monomers (chain D).
- PIRSF036517 (Ext_hemo)