Structure of Mutant Human Carbonmonoxyhemoglobin C (beta E6K) at 2.0 Angstrom Resolution in Phosphate Buffer.
[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.    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. 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.
Publication Abstract from PubMed
Previous studies have demonstrated that in vitro crystallization of R-state liganded hemoglobin C (HbC), a naturally occurring mutant human hemoglobin (betaE6K), in high-phosphate buffer solutions provides a potential model system for the intracellular crystallization of HbC associated with chronic hemolytic anemia in CC disease. The first high-resolution crystal structure of liganded HbC is reported here. HbC was crystallized from high phosphate and the structure of the carbonmonoxy-liganded R-state form was refined at 2.0 A resolution. Crystals exhibit diffraction consistent with the tetragonal space group P4(1)2(1)2, with unit-cell parameters a = 54.16, c = 195.30 A. The structure was solved by difference Fourier techniques and refinement by simulated annealing and restrained least-squares yielded a final R of 0.183 and an R(free) of 0.238 for all 19,382 unique reflections. The side chain of betaK6 exhibits very weak electron density consistent with significant mobility within the crystalline lattice. The highly dynamic nature of the side chain could potentially support a number of specific polar interactions that might reduce the barrier to crystallization and thus result in enhanced crystallization kinetics for HbC relative to HbA. Specifically, the NZ atom of the BK6 side chain could participate in an amino-aromatic hydrogen bond with the pi-electron cloud of betaH116 in a symmetry-related tetramer. BetaK6 NZ might also interact with the main-chain carbonyl O atom of betaH117 and the carboxylate group of betaE22 from a symmetry-related tetramer.
Structure of mutant human carbonmonoxyhemoglobin C (betaE6K) at 2.0 A resolution.,Dewan JC, Feeling-Taylor A, Puius YA, Patskovska L, Patskovsky Y, Nagel RL, Almo SC, Hirsch RE Acta Crystallogr D Biol Crystallogr. 2002 Dec;58(Pt 12):2038-42. Epub 2002, Nov 23. PMID:12454462
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.