PROSITE documentation PDOC00793

Globin family and Androglobin (Adgb) circularly permuted globin domain profiles

Globins are small metalloproteins that typically comprise around 150 amino acids, but may also have N- and/or C-terminal extensions. Most globins cover eight α-helical segments (named A through H) with a characteristic 3-over-3 α-helical sandwich structure (referred to as globin fold) and include a haem prosthetic group (Fe(2+)-protoporphyrin IX), by which they reversibly bind oxygen, and in some cases, also other ligands. While their overall structures are conserved, globin primary sequences often are not. In fact, only the proximal histidine (position F8; i.e. 8th amino acid in helix F) adjacent to the Fe(2+) is present in all globins, and most of them also show a phenylalanine in inter-helical region CD1, which stabilizes the haem. Globins are found in all domains of life and mainly perform cellular functions involving the storage, transport, and enzymatic detoxification of gaseous ligands [1,2]. The major groups of globins are:

• Hemoglobins (Hb) from vertebrates. Hb is the protein responsible for transporting oxygen from the lungs to other tissues. It is a tetramer of two α and two β chains. Most vertebrate species also express specific embryonic or fetal forms of hemoglobin where the α or the β chains are replaced by a chain with higher oxygen affinity, as for the γ, delta, epsilon and zeta chains in mammals, for example.
• Myoglobins (Mg) from vertebrates. Mg is a monomeric protein responsible for oxygen storage in muscles.
• Neuroglobins (Ngb) from vertebrates. Ngb is a nerve globin that may play a role in local or temporal O(2) supply or protection from reactive oxygen species (ROS).
• Cytoglobins (Cygb) from vertebrates. Cygb is a tissue globin with roles in nitric oxide (NO) metabolism, fibrosis and tumourigenesis.
• Androglobins (Adgb) from Metazoans and choanoflagellates. Adgb has a unique modular architecture, possessing an N-terminal calpain-like domain (see <PDOC50203>), an internal, circular permuted globin domain, and an IQ calmodulin-binding motif (see <PDOC50096>). The globin domain, which normally consists of eight consecutive α-helices (named A-H), is circularly permutated and split into two parts within Adgb. The part containing helices A and B has been shifted in the C-terminal direction and is separated from the main globin sequence (helices C-H) by a calmodulin- binding IQ motif [3,4].
• Invertebrate globins [5]. A wide variety of globins are found in invertebrates. Molluscs generally have one or two muscle globins which are either monomeric or dimeric. Insects, such as the midge Chironomus thummi, have a large set of extracellular globins. Nematodes and annelids have a variety of intracellular and extracellular globins; some of them are multi- domain polypeptides (from two up to nine-domain globins) and some produce large, disulfide-bonded aggregates.
• Leghemoglobins (Lg) from the root nodules of leguminous plants. Lg provides oxygen for bacteroids.
• Flavohemoproteins from bacteria (Escherichia coli hmpA) and fungi. These proteins consist of two distinct domains: an N-terminal globin domain and a C-terminal FAD-containing reductase domain. In bacteria such as Vitreoscilla, the enzyme-associated globin is a single domain protein.

All these globins seem to have evolved from a common ancestor. The profile developed to detect members of the globin family is based on a structural alignment of selected globin sequences. We developed a second profile for the circularly permuted globin domain of Adgb proteins.