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Molecular mechanism of AHSP-mediated stabilization of alpha-hemoglobin


Feng, L and Gell, DA and Zhou, S and Gu, L and Kong, Y and Li, J and Hu, M and Nan, N and Lee, C and Rich, AM and Armstrong, RS and Lay, PA and Gow, AJ and Weiss, MJ and Mackay, JP and Shi, Y, Molecular mechanism of AHSP-mediated stabilization of alpha-hemoglobin, Cell, 119, (5) pp. 629-640. ISSN 0092-8674 (2004) [Refereed Article]

DOI: doi:10.1016/j.cell.2004.11.025


Hemoglobin A (HbA), the oxygen delivery system in humans, comprises two α and two β subunits. Free α-hemoglobin (αHb) is unstable, and its precipitation contributes to the pathophysiology of β thalassemia. In erythrocytes, the α-hemoglobin stabilizing protein (AHSP) binds αHb and inhibits its precipitation. The crystal structure of AHSP bound to Fe(II)-αHb reveals that AHSP specifically recognizes the G and H helices of αHb through a hydrophobic interface that largely recapitulates the α1-β1 interface of hemoglobin. The AHSP-αHb interactions are extensive but suboptimal, explaining why β-hemoglobin can competitively displace AHSP to form HbA. Remarkably, the Fe(II)-heme group in AHSP bound αHb is coordinated by the distal but not the proximal histidine. Importantly, binding to AHSP facilitates the conversion of oxy-αHb to a deoxygenated, oxidized [Fe(III)], nonreactive form in which all six coordinate positions are occupied. These observations reveal the molecular mechanisms by which AHSP stabilizes free αHb.

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
UTAS Author:Gell, DA (Dr David Gell)
ID Code:64548
Year Published:2004
Web of Science® Times Cited:125
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-08-12
Last Modified:2011-08-01

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