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Human zeta-2 beta-2-s hemoglobinHuman zeta-2 beta-2-s hemoglobin
Structural highlights
Disease[HBB_HUMAN] Defects in HBB 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] [2] [3] [4] Defects in HBB are the cause of beta-thalassemia (B-THAL) [MIM:613985]. A form of thalassemia. Thalassemias are common monogenic diseases occurring mostly in Mediterranean and Southeast Asian populations. The hallmark of beta-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. Absence of beta chain causes beta(0)-thalassemia, while reduced amounts of detectable beta globin causes beta(+)-thalassemia. In the severe forms of beta-thalassemia, the excess alpha globin chains accumulate in the developing erythroid precursors in the marrow. Their deposition leads to a vast increase in erythroid apoptosis that in turn causes ineffective erythropoiesis and severe microcytic hypochromic anemia. Clinically, beta-thalassemia is divided into thalassemia major which is transfusion dependent, thalassemia intermedia (of intermediate severity), and thalassemia minor that is asymptomatic.[5] Defects in HBB are the cause of sickle cell anemia (SKCA) [MIM:603903]; also known as sickle cell disease. Sickle cell anemia is characterized by abnormally shaped red cells resulting in chronic anemia and periodic episodes of pain, serious infections and damage to vital organs. Normal red blood cells are round and flexible and flow easily through blood vessels, but in sickle cell anemia, the abnormal hemoglobin (called Hb S) causes red blood cells to become stiff. They are C-shaped and resembles a sickle. These stiffer red blood cells can led to microvascular occlusion thus cutting off the blood supply to nearby tissues. Defects in HBB are the cause of beta-thalassemia dominant inclusion body type (B-THALIB) [MIM:603902]. An autosomal dominant form of beta thalassemia characterized by moderate anemia, lifelong jaundice, cholelithiasis and splenomegaly, marked morphologic changes in the red cells, erythroid hyperplasia of the bone marrow with increased numbers of multinucleate red cell precursors, and the presence of large inclusion bodies in the normoblasts, both in the marrow and in the peripheral blood after splenectomy.[6] Function[HBAZ_HUMAN] The zeta chain is an alpha-type chain of mammalian embryonic hemoglobin, synthesized primarily in the yolk sac. [HBB_HUMAN] Involved in oxygen transport from the lung to the various peripheral tissues.[7] LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.[8] Publication Abstract from PubMedA variant Hb zeta2beta2(s) that is formed from sickle hemoglobin (Hb S; alpha2beta2(s)) by exchanging adult alpha-globin with embryonic zeta-globin subunits shows promise as a therapeutic agent for sickle-cell disease (SCD). Hb zeta2beta2(s) inhibits the polymerization of deoxygenated Hb S in vitro and reverses characteristic features of SCD in vivo in mouse models of the disorder. When compared with either Hb S or with normal human adult Hb A (alpha2beta2), Hb zeta2beta2(s) exhibits atypical properties that include a high oxygen affinity, reduced cooperativity, a weak Bohr effect and blunted 2,3-diphosphoglycerate allostery. Here, the 1.95 A resolution crystal structure of human Hb zeta2beta2(s) that was expressed in complex transgenic knockout mice and purified from their erythrocytes is presented. When fully liganded with carbon monoxide, Hb zeta2beta2(s) displays a central water cavity, a zeta1-beta(s)2 (or zeta2-beta(s)1) interface, intersubunit salt-bridge/hydrogen-bond interactions, C-terminal betaHis146 salt-bridge interactions, and a beta-cleft, that are highly unusual for a relaxed hemoglobin structure and are more typical of a tense conformation. These quaternary tense-like features contrast with the tertiary relaxed-like conformations of the zeta1beta(s)1 dimer and the CD and FG corners, as well as the overall structures of the heme cavities. This crystallographic study provides insights into the altered oxygen-transport properties of Hb zeta2beta2(s) and, moreover, decouples tertiary- and quaternary-structural events that are critical to Hb ligand binding and allosteric function. Structure of fully liganded Hb zeta2beta2(s) trapped in a tense conformation.,Safo MK, Ko TP, Abdulmalik O, He Z, Wang AH, Schreiter ER, Russell JE Acta Crystallogr D Biol Crystallogr. 2013 Oct;69(Pt 10):2061-71. doi:, 10.1107/S0907444913019197. Epub 2013 Sep 20. PMID:24100324[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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