Globin superfamily members share a common three-dimensional fold.[3] This 'globin fold' typically consists of eight alpha helices, although some proteins have additional helix extensions at their termini.[4] 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 (myoglobin was the first protein whose structure was solved).
Helix packaging
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 acid side chains near the helix interfaces.
Evolution
Globins evolved from a common ancestor and can be divided into three lineages:[5][6]
Family M (for myoglobin-like) or F (for FHb-like),[7] which has a typical 3/3 fold.
Subfamily SDgb, for single-domain globins (not to be confused with SSDgb).
Family S (for sensor-like), again with a 3/3 fold.
Subfamily GCS, for Globin-coupled sensors. Chimeric.
Subfamily PGb, for protoglobins. Single-domain.
Subfamily SSDgb, for sensor single-domain globins.
Family T (for truncated), with a 2/2 fold[8] All subfamilies can be chimeric, single-domain, or tandemly linked.[7]
Subfamily TrHb1 (also T1 or N).
Subfamily TrHb2 (also T2 or O). Includes 2/2 phytoglobins.
Subfamily TrHb3 (also T3 or P).
The M/F family of globins is absent in archaea. Eukaryotes lack GCS, Pgb, and T3 subfamily globins.[7]
Eight globins are known to occur in vertebrates: androglobin (Adgb), cytoglobin (Cygb), globin E (GbE, from bird eye), globin X (GbX, not found in mammals or birds), globin Y (GbY, from some mammals), hemoglobin (Hb), myoglobin (Mb) and neuroglobin (Ngb).[7] All these types evolved from a single globin gene of F/M family[7] found in basal animals.[9] The single gene has also invented an oxygen-carrying "hemoglobin" multiple times in other groups of animals.[10] Several functionally different haemoglobins can coexist in the same species.
Sequence conservation
Although the fold of the globin superfamily is highly evolutionarilyconserved, 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].
Neuroglobin: a myoglobin-like haemprotein expressed in vertebrate brain and retina, where it is involved in neuroprotection from damage due to hypoxia or ischemia.[11] Neuroglobin belongs to a branch of the globin family that diverged early in evolution.
Non-symbiotic haemoglobin (NsHb): occurs in non-leguminous plants, and can be over-expressed in stressed plants .
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.[14]
Globin E: a globin responsible for storing and delivering oxygen to the retina in birds[15]
Globin-coupled sensors: chimeric, with an N-terminal myoglobin-like domain and a C-terminal domain that resembles the cytoplasmicsignalling domain of bacterial chemoreceptors. They bind oxygen, and act to initiate an aerotactic response or regulategene expression.[16][17]
Protoglobin: a single domain globin found in archaea that is related to the N-terminal domain of globin-coupled sensors.[18]
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.
HbN (or GlbN): 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.[19]
Cyanoglobin (or GlbN): 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.[20]
HbO (or GlbO): 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.[21]
Glb3: a nuclear-encoded truncated haemoglobin from plants that appears more closely related to HbO than HbN. Glb3 from Arabidopsis thaliana (Mouse-ear cress) exhibits an unusual concentration-independent binding of oxygen and carbon dioxide.[22]
^Kavanaugh JS, Rogers PH, Case DA, Arnone A (April 1992). "High-resolution X-ray study of deoxyhemoglobin Rothschild 37 beta Trp----Arg: a mutation that creates an intersubunit chloride-binding site". Biochemistry. 31 (16): 4111–21. doi:10.1021/bi00131a030. PMID1567857.
^Vinogradov SN, Hoogewijs D, Bailly X, Mizuguchi K, Dewilde S, Moens L, Vanfleteren JR (August 2007). "A model of globin evolution". Gene. 398 (1–2): 132–42. doi:10.1016/j.gene.2007.02.041. PMID17540514.
^Branden, Carl; Tooze, John (1999). Introduction to protein structure (2nd ed.). New York: Garland Pub. ISBN978-0815323051.
^Bolognesi, M; Onesti, S; Gatti, G; Coda, A; Ascenzi, P; Brunori, M (1989). "Aplysia limacina myoglobin. Crystallographic analysis at 1.6 a resolution". Journal of Molecular Biology. 205 (3): 529–44. doi:10.1016/0022-2836(89)90224-6. PMID2926816.
^Freitas TA, Saito JA, Hou S, Alam M (January 2005). "Globin-coupled sensors, protoglobins, and the last universal common ancestor". J. Inorg. Biochem. 99 (1): 23–33. doi:10.1016/j.jinorgbio.2004.10.024. PMID15598488.
^Yeh DC, Thorsteinsson MV, Bevan DR, Potts M, La Mar GN (February 2000). "Solution 1H NMR study of the heme cavity and folding topology of the abbreviated chain 118-residue globin from the cyanobacterium Nostoc commune". Biochemistry. 39 (6): 1389–99. doi:10.1021/bi992081l. PMID10684619.
