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Role of alpha hemoglobin-stabilizing protein in normal erythropoiesis and beta-thalassemia

Citation

Weiss, MJ and Zhou, S and Feng, L and Gell, DA and Mackay, JP and Shi, Y and Gow, AJ, Role of alpha hemoglobin-stabilizing protein in normal erythropoiesis and beta-thalassemia, New York Academy of Sciences. Annals, 1054, (1) pp. 103-117. ISSN 0077-8923 (2005) [Refereed Article]

DOI: doi:10.1196/annals.1345.013

Abstract

Hemoglobin (Hb) synthesis is coordinated by homeostatic mechanisms to limit the accumulation of free α or β subunits, which are cytotoxic. Alpha hemoglobin-stabilizing protein (AHSP) is an abundant erythroid protein that specifically binds free αHb, stabilizes its structure, and limits its ability to participate in chemical reactions that generate reactive oxygen species. Gene ablation studies in mice demonstrate that AHSP is required for normal erythropoiesis. AHSP-null erythrocytes are short-lived, contain Hb precipitates, and exhibit signs of oxidative damage. Loss of AHSP exacerbates β-thalassemia in mice, indicating that altered AHSP expression or function could modify thalassemia phenotypes in humans, a topic that is beginning to be explored in clinical studies. We used biochemical, spectroscopic, and crystallographic methods to examine how AHSP stabilizes αHb. AHSP binds the G and H helices of αHb on a surface that largely overlaps with the α1-β1 interface of HbA. This result explains previous findings that βHb can competitively displace AHSP from αHb to form HbA tetramer. Remarkably, binding of AHSP to oxygenated αHb induces dramatic conformational changes and converts the heme-bound iron to an oxidized hemichrome state in which all six coordinate positions are occupied. This structure limits the reactivity of heme iron, providing a mechanism by which AHSP stabilizes αHb. These findings suggest a biochemical pathway through which AHSP might participate in normal Hb synthesis and modulate the severity of thalassemias. Moreover, understanding how AHSP stabilizes αHb provides a theoretical basis for new strategies to inhibit the damaging effects of free αHb that accumulates in β-thalassemia. 2005 New York Academy of Sciences.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Structural Biology (incl. Macromolecular Modelling)
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Biological Sciences
Author:Gell, DA (Dr David Gell)
ID Code:64536
Year Published:2005
Web of Science® Times Cited:29
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-08-12
Last Modified:2012-03-06
Downloads:0

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