3s48
Human Alpha-Haemoglobin Complexed with the First NEAT Domain of IsdH from Staphylococcus aureusHuman Alpha-Haemoglobin Complexed with the First NEAT Domain of IsdH from Staphylococcus aureus
Structural highlights
Disease[HBA_HUMAN] Defects in HBA1 may be a cause of Heinz body anemias (HEIBAN) [MIM:140700]. This is a form of non-spherocytic hemolytic anemia of Dacie type 1. After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies) and with glutathione peroxidase deficiency.[1] Defects in HBA1 are the cause of alpha-thalassemia (A-THAL) [MIM:604131]. The thalassemias are the most common monogenic diseases and occur mostly in Mediterranean and Southeast Asian populations. The hallmark of alpha-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. The level of alpha chain production can range from none to very nearly normal levels. Deletion of both copies of each of the two alpha-globin genes causes alpha(0)-thalassemia, also known as homozygous alpha thalassemia. Due to the complete absence of alpha chains, the predominant fetal hemoglobin is a tetramer of gamma-chains (Bart hemoglobin) that has essentially no oxygen carrying capacity. This causes oxygen starvation in the fetal tissues leading to prenatal lethality or early neonatal death. The loss of three alpha genes results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia known as hemoglobin H disease. Untreated, most patients die in childhood or early adolescence. The loss of two alpha genes results in mild alpha-thalassemia, also known as heterozygous alpha-thalassemia. Affected individuals have small red cells and a mild anemia (microcytosis). If three of the four alpha-globin genes are functional, individuals are completely asymptomatic. Some rare forms of alpha-thalassemia are due to point mutations (non-deletional alpha-thalassemia). The thalassemic phenotype is due to unstable globin alpha chains that are rapidly catabolized prior to formation of the alpha-beta heterotetramers. Note=Alpha(0)-thalassemia is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. Defects in HBA1 are the cause of hemoglobin H disease (HBH) [MIM:613978]. HBH is a form of alpha-thalassemia due to the loss of three alpha genes. This results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia. Untreated, most patients die in childhood or early adolescence.[2] Function[ISDH_STAAS] Binds human plasma haptoglobin-hemoglobin complexes, haptoglobin and hemoglobin. Binds haptoglobin-hemoglobin complexes with significantly higher affinity than haptoglobin alone (Probable). [HBA_HUMAN] Involved in oxygen transport from the lung to the various peripheral tissues. Publication Abstract from PubMedAdult haemoglobin (Hb) is made up of two alpha and two beta subunits. Mutations that reduce expression of the alpha- or beta-globin genes lead to the conditions alpha- or beta-thalassaemia, respectively. Whilst both conditions are characterized by anaemia of variable severity, other details of their pathophysiology are different, in part owing to the greater stability of the beta chains that is conferred through beta self-association. In contrast, alpha subunits interact weakly, and in the absence of stabilizing quaternary interactions the alpha chain (alpha) is prone to haem loss and denaturation. The molecular contacts that confer weak self-association of alpha have not been determined previously. Here, the first structure of an alpha2 homodimer is reported in complex with one domain of the Hb receptor from Staphylococcus aureus. The alpha2 dimer interface has a highly unusual, approximately linear, arrangement of four His side chains within hydrogen-bonding distance of each other. Some interactions present in the alpha1beta1 dimer interface of native Hb are preserved in the alpha2 dimer. However, a marked asymmetry is observed in the alpha2 interface, suggesting that steric factors limit the number of stabilizing interactions that can form simultaneously across the interface. The structure of alpha-haemoglobin in complex with a haemoglobin-binding domain from Staphylococcus aureus reveals the elusive alpha-haemoglobin dimerization interface.,Krishna Kumar K, Jacques DA, Guss JM, Gell DA Acta Crystallogr F Struct Biol Commun. 2014 Aug 1;70(Pt 8):1032-7. doi:, 10.1107/S2053230X14012175. Epub 2014 Jul 23. PMID:25084376[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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