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Crystal Structures of HbA2 and HbE and Modeling of Hemoglobin δ4:  Interpretation of the Thermal Stability and the Antisickling Effect of HbA2 and Identification of the Ferrocyanide Binding Site in Hb
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    Crystal Structures of HbA2 and HbE and Modeling of Hemoglobin δ4:  Interpretation of the Thermal Stability and the Antisickling Effect of HbA2 and Identification of the Ferrocyanide Binding Site in Hb
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    Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700064, India, Biophysics Division, Saha Institute of Nuclear Physics, 37 Belgachia Road, Kolkata 700037, India, and Thalassemia Hospital, 19B Chetlahat Road, Kolkata 700027, India
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    Biochemistry

    Cite this: Biochemistry 2004, 43, 39, 12477–12488
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    https://doi.org/10.1021/bi048903i
    Published September 11, 2004
    Copyright © 2004 American Chemical Society

    Abstract

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    Hemoglobin A22δ2) is an important hemoglobin variant which is a minor component (2−3%) in the circulating red blood cells, and its elevated concentration in β-thalassemia is a useful clinical diagnostic. In β-thalassemia major, where there is β-chain production failure, HbA2 acts as the predominant oxygen deliverer. HbA2 has two more important features. (1) It is more resistant to thermal denaturation than HbA, and (2) it inhibits the polymerization of deoxy sickle hemoglobin (HbS). Hemoglobin E (E26Kβ), formed as a result of the splice site mutation on exon 1 of the β-globin gene, is another important hemoglobin variant which is known to be unstable at high temperatures. Both heterozygous HbE (HbAE) and homozygous HbE (HbEE) are benign disorders, but when HbE combines with β-thalassemia, it causes E/β-thalassemia which has severe clinical consequences. In this paper, we present the crystal structures of HbA2 and HbE at 2.20 and 1.74 Å resolution, respectively, in their R2 states, which have been used here to provide the probable explanations of the thermal stability and instability of HbA2 and HbE. Using the coordinates of R2 state HbA2, we modeled the structure of T state HbA2 which allowed us to address the structural basis of the antisickling property of HbA2. Using the coordinates of the δ-chain of HbA2 (R2 state), we also modeled the structure of hemoglobin homotetramer δ4 that occurs in the case of rare HbH disease. From the differences in intersubunit contacts among β4, γ4, and δ4, we formed a hypothesis regarding the possible tetramerization pathway of δ4. The crystal structure of a ferrocyanide-bound HbA2 at 1.88 Å resolution is also presented here, which throws light on the location and the mode of binding of ferrocyanide anion with hemoglobin, predominantly using the residues involved in DPG binding. The pH dependence of ferrocyanide binding with hemoglobin has also been investigated.

    Copyright © 2004 American Chemical Society

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     The coordinates of HbE, HbA2, and HbA2FC have been submitted to the RCSB as entries 1NQP, 1SI4, and 1SHR, respectively.

    §

     Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics.

     Biophysics Division, Saha Institute of Nuclear Physics.

     Thalassemia Hospital.

    *

     To whom correspondence should be addressed. Telephone: +91-033-2321-4986. Fax:  +91-033-2337-4637. E-mail:  jiban@ cmb2.saha.ernet.in.

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    Two 2FoFc electron density maps around δ-chain residues of HbA2 and stereoscopic representation of the mode of ferrocyanide binding in HbA2FC. This material is available free of charge via the Internet at http://pubs.acs.org.

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    22. Martin H. Steinberg, Griffin P. Rodgers. HbA 2 : biology, clinical relevance and a possible target for ameliorating sickle cell disease. British Journal of Haematology 2015, 170 (6) , 781-787. https://doi.org/10.1111/bjh.13570
    23. Deboshree M. Bhattacharyya, Jayasri Basak, Soma Mukhopadhyay, Ashis Mukhopadhyay. Status of HbE variant among Rabha tribe of West Bengal, India. Indian Journal of Medical Research 2015, 141 (5) , 521-524. https://doi.org/10.4103/0971-5916.159505
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    26. Deboshree M. Bhattacharyya, Ashis Mukhopadhyay, Jayasri Basak. Descriptive profile of β-thalassemia mutations in West Bengal population: a hospital-based study. International Journal of Hematology 2014, 99 (3) , 345-353. https://doi.org/10.1007/s12185-014-1511-4
    27. Abhijit Chakrabarti, Dipankar Bhattacharya, Sanghamitra Deb, Madhumita Chakraborty, . Differential Thermal Stability and Oxidative Vulnerability of the Hemoglobin Variants, HbA2 and HbE. PLoS ONE 2013, 8 (11) , e81820. https://doi.org/10.1371/journal.pone.0081820
    28. Bahri İnce, Sinan Guloksuz, Kürşat Altınbaş, Esat Timuçin Oral, Latif Ruhşat Alpkan, Meric A. Altinoz. Minor hemoglobins HbA2 and HbF associate with disease severity in bipolar disorder with a likely protective role of HbA2 against post-partum episodes. Journal of Affective Disorders 2013, 151 (1) , 405-408. https://doi.org/10.1016/j.jad.2013.06.042
    29. Deboshree Bhattacharyya, Ashis Mukhopadhyay, Abhijit Chakraborty, Swati Dasgupta, Soma Mukhopadhyay, Nabamita Pal, Jayasri Basak. Incidence of the Hb E [β26(B8)Glu→Lys, G AG> A AG] Variant In Totos, One of the Smallest Primitive Tribes in the World. Hemoglobin 2013, 37 (1) , 26-36. https://doi.org/10.3109/03630269.2012.746942
    30. Qiuying Chen, Mary E. Fabry, Anne C. Rybicki, Sandra M. Suzuka, Tatiana C. Balazs, Zipora Etzion, Kitty de Jong, Edna K. Akoto, Joseph E. Canterino, Dhananjay K. Kaul, Frans A. Kuypers, David Lefer, Eric E. Bouhassira, Rhoda Elison Hirsch. A transgenic mouse model expressing exclusively human hemoglobin E: Indications of a mild oxidative stress. Blood Cells, Molecules, and Diseases 2012, 48 (2) , 91-101. https://doi.org/10.1016/j.bcmd.2011.12.002
    31. Mousumi Banerjee, Malini Pramanik, Dipankar Bhattacharya, Mohini Lahiry, Samita Basu, Abhjit Chakrabarti. Faster heme loss from hemoglobin E than HbS, in acidic pH: Effect of aminophospholipids. Journal of Biosciences 2011, 36 (5) , 809-816. https://doi.org/10.1007/s12038-011-9163-5
    32. Camille J. Roche, Vladimir Malashkevich, Tatiana C. Balazs, David Dantsker, Qiuying Chen, Juan Moreira, Steven C. Almo, Joel M. Friedman, Rhoda Elison Hirsch. Structural and Functional Studies Indicating Altered Redox Properties of Hemoglobin E. Journal of Biological Chemistry 2011, 286 (26) , 23452-23466. https://doi.org/10.1074/jbc.M110.183186
    33. Dipankar Bhattacharya, Sutapa Saha, Sumanta Basu, Sudipa Chakravarty, Amit Chakravarty, Debashis Banerjee, Abhijit Chakrabarti. Differential regulation of redox proteins and chaperones in HbEβ‐thalassemia erythrocyte proteome. PROTEOMICS – Clinical Applications 2010, 4 (5) , 480-488. https://doi.org/10.1002/prca.200900073
    34. Haiyan Xiao, Ping Zhu, Beiyi Liu, Qingjun Pan, Xiaotao Jiang, Xiangmin Xu, Ning Fu. Generation and characterization of human δ-globin-specific monoclonal antibodies. Blood Cells, Molecules, and Diseases 2010, 44 (3) , 127-132. https://doi.org/10.1016/j.bcmd.2009.11.003
    35. . THE MOLECULAR, CELLULAR, AND GENETIC BASIS OF HEMOGLOBIN DISORDERS. 2009, 1-2. https://doi.org/10.1017/CBO9780511596582.004
    36. Martin H. Steinberg, Ronald L. Nagel. Hemoglobins of the Embryo, Fetus, and Adult. 2009, 119-136. https://doi.org/10.1017/CBO9780511596582.011
    37. Abhijit Chakrabarti. A Fluorescence Quenching Method to Study Interactions of Hemoglobin Derivatives with Erythroid Spectrin. 2009, 363-377. https://doi.org/10.1007/978-0-387-88722-7_15
    38. Abhijit Chakrabarti, Poppy Datta, Dipankar Bhattacharya, Sumanta Basu, Sutapa Saha. Oxidative crosslinking, spectrin and membrane interactions of hemoglobin mixtures in HbE β -thalassemia. Hematology 2008, 13 (6) , 361-368. https://doi.org/10.1179/102453308X343455
    39. Poppy Datta, Sudipa Chakrabarty, Amit Chakrabarty, Abhijit Chakrabarti. Membrane interactions of hemoglobin variants, HbA, HbE, HbF and globin subunits of HbA: Effects of aminophospholipids and cholesterol. Biochimica et Biophysica Acta (BBA) - Biomembranes 2008, 1778 (1) , 1-9. https://doi.org/10.1016/j.bbamem.2007.08.019
    40. Dipankar Bhattacharya, Debashis Mukhopadhyay, Abhijit Chakrabarti. Hemoglobin depletion from red blood cell cytosol reveals new proteins in 2‐D gel‐based proteomics study. PROTEOMICS – Clinical Applications 2007, 1 (6) , 561-564. https://doi.org/10.1002/prca.200700178
    41. Poppy Datta, Sumanta Basu, Sudipa Basu Chakravarty, Amit Chakravarty, Debashis Banerjee, Sharmila Chandra, Abhijit Chakrabarti. Enhanced oxidative cross-linking of hemoglobin E with spectrin and loss of erythrocyte membrane asymmetry in hemoglobin Eβ-thalassemia. Blood Cells, Molecules, and Diseases 2006, 37 (2) , 77-81. https://doi.org/10.1016/j.bcmd.2006.06.001
    42. Karin Zurbriggen, Markus Schmugge, Marlis Schmid, Silke Durka, Peter Kleinert, Thomas Kuster, Claus W Heizmann, Heinz Troxler. Analysis of Minor Hemoglobins by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Clinical Chemistry 2005, 51 (6) , 989-996. https://doi.org/10.1373/clinchem.2005.047985

    Biochemistry

    Cite this: Biochemistry 2004, 43, 39, 12477–12488
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi048903i
    Published September 11, 2004
    Copyright © 2004 American Chemical Society

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