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Molecular mechanism of AHSP-mediated stabilization of alpha-hemoglobin
journal contribution
posted on 2023-05-17, 02:58 authored by Feng, L, David GellDavid Gell, Zhou, S, Gu, L, Kong, Y, Li, J, Hu, M, Nan, N, Lee, C, Rich, AM, Armstrong, RS, Lay, PA, Gow, AJ, Weiss, MJ, Mackay, JP, Shi, YHemoglobin 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.
History
Publication title
CellVolume
119Issue
5Pagination
629-640ISSN
0092-8674Department/School
Menzies Institute for Medical ResearchPublisher
Cell PressPlace of publication
1100 Massachusetts Ave, Cambridge, USA, Ma, 02138Repository Status
- Restricted