Members of this entry include the growth hormone and erythropoietin receptors. The latter interacts with erythropoietin (EPO), with subsequent initiation of the downstream chain of events associated with binding of EPO to the receptor, including EPO-induced erythroblast proliferation and differentiation through induction of the JAK2/STAT5 signalling cascade. The domain adopts a secondary structure composed of a short amino-terminal helix, followed by two β-sandwich regions [].
Erythropoietin, a plasma glycoprotein, is the primary physiological mediator of erythropoiesis []. Itis involved in the regulation of the level of peripheral erythrocytes by stimulating the differentiation of erythroid progenitor cells, found in the spleen and bone marrow, into mature erythrocytes []. It is primarily produced in adult kidneys and foetal liver, acting by attachment to specific binding sites on erythroid progenitor cells, stimulating their differentiation []. Severe kidney dysfunction causes reduction in the plasma levels of erythropoietin,resulting in chronic anaemia - injection of purified erythropoietin into the blood stream can help to relieve this type of anaemia. Levels of erythropoietin in plasma fluctuate with varying oxygen tension of the blood, but androgens and prostaglandins also modulate the levels to some extent []. Erythropoietin glycoprotein sequences are well conserved, a consequence of which is that the hormones are cross-reactive among mammals,i.e. that from one species, say human, can stimulate erythropoiesis inother species, say mouse or rat []. Thrombopoeitin (TPO), a glycoprotein, is the mammalian0 hormone which functions as a megakaryocytic lineage specific growth and differentiation factor affecting the proliferation and maturation from their committed progenitor cells acting at a late stage of megakaryocyte development. It acts as a circulating regulator of platelet numbers.EPO and TPO are evolutionary related. As a signature pattern, this entry represents a conserved region located at the N-terminal extremity of mature EPO and TPO and that includes two cysteines which have been shown, in human EPO, to be implicated in disulphide bonds.
Peroxidases are haem-containing enzymes that use hydrogen peroxide as the electron acceptor to catalyse a number of oxidative reactions.Peroxidases are found in bacteria, fungi, plants and animals. On the basis of sequence similarity, a number of animal haem peroxidases can be categorised as members of a superfamily: myeloperoxidase (MPO); eosinophil peroxidase (EPO); lactoperoxidase (LPO); thyroid peroxidase (TPO); prostaglandin H synthase (PGHS); and peroxidasin [, , ]. MPO plays a major role in the oxygen-dependent microbicidal system of neutrophils. EPO from eosinophilic granulocytes participates in immunological reactions, and potentiates tumor necrosis factor (TNF) production and hydrogen peroxide release by human monocyte-derived macrophages [, ]. In the main, MPO (and possibly EPO) utilises Cl-ions and H2O2to form hypochlorous acid (HOCl), which can effectively kill bacteria or parasites. In secreted fluids, LPO catalyses the oxidation of thiocyanate ions (SCN-) by H2O2, producing the weak oxidising agent hypothiocyanite (OSCN-), which has bacteriostatic activity []. TPO uses I-ions and H2O2to generate iodine, and plays a central role in the biosynthesis of thyroid hormones T(3) and T(4). To date, the 3D structures of MPO and PGHS have been reported. MPO is a homodimer: each monomer consists of a light (A or B) and a heavy (C or D) chain resulting from post-translational excision of 6 residues from the common precursor. Monomers are linked by a single inter-chain disulphide. Each monomer includes a bound calcium ion []. PGHS exists as a symmetric dimer, each monomer of which consists of 3 domains: an N-terminal epidermal growth factor (EGF) like module; a membrane-binding domain; and a large C-terminal catalytic domain containing the cyclooxygenase and the peroxidase active sites. The catalytic domain shows striking structural similarity to MPO. The cyclooxygenase active site, which catalyses the formation of prostaglandin G2 (PGG2) from arachidonic acid, resides at the apex of a long hydrophobic channel, extending from the membrane-binding domain to the centre of the molecule. The peroxidase active site, which catalyses the reduction of PGG2 to PGH2, is located on the other side of the molecule, at the haem binding site []. Both MPO and the catalytic domain of PGHS are mainly α-helical, 19 helices being identified as topologically and spatially equivalent; PGHS contains 5 additional N-terminal helices that have no equivalent in MPO. In both proteins, three Asn residues in each monomer are glycosylated.
Peroxidases are haem-containing enzymes that use hydrogen peroxide as the electron acceptor to catalyse a number of oxidative reactions.Peroxidases are found in bacteria, fungi, plants and animals. On the basis of sequence similarity, a number of animal haem peroxidases can be categorised as members of a superfamily: myeloperoxidase (MPO); eosinophil peroxidase (EPO); lactoperoxidase (LPO); thyroid peroxidase (TPO); prostaglandin H synthase (PGHS); and peroxidasin [, , ]. MPO plays a major role in the oxygen-dependent microbicidal system of neutrophils. EPO from eosinophilic granulocytes participates in immunological reactions, and potentiates tumor necrosis factor (TNF) production and hydrogen peroxide release by human monocyte-derived macrophages [, ]. In the main, MPO (and possibly EPO) utilises Cl-ions and H2O2to form hypochlorous acid (HOCl), which can effectively kill bacteria or parasites. In secreted fluids, LPO catalyses the oxidation of thiocyanate ions (SCN-) by H2O2, producing the weak oxidising agent hypothiocyanite (OSCN-), which has bacteriostatic activity []. TPO uses I-ions and H2O2to generate iodine, and plays a central role in the biosynthesis of thyroid hormones T(3) and T(4). To date, the 3D structures of MPO and PGHS have been reported. MPO is a homodimer: each monomer consists of a light (A or B) and a heavy (C or D) chain resulting from post-translational excision of 6 residues from the common precursor. Monomers are linked by a single inter-chain disulphide. Each monomer includes a bound calcium ion []. PGHS exists as a symmetric dimer, each monomer of which consists of 3 domains: an N-terminal epidermal growth factor (EGF) like module; a membrane-binding domain; and a large C-terminal catalytic domain containing the cyclooxygenase and the peroxidase active sites. The catalytic domain shows striking structural similarity to MPO. The cyclooxygenase active site, which catalyses the formation of prostaglandin G2 (PGG2) from arachidonic acid, resides at the apex of a long hydrophobic channel, extending from the membrane-binding domain to the centre of the molecule. The peroxidase active site, which catalyses the reduction of PGG2 to PGH2, is located on the other side of the molecule, at the haem binding site []. Both MPO and the catalytic domain of PGHS are mainly α-helical, 19 helices being identified as topologically and spatially equivalent; PGHS contains 5 additional N-terminal helices that have no equivalent in MPO. In both proteins, three Asn residues in each monomer are glycosylated.
