TY - JOUR
T1 - Molecular mechanism of AHSP-mediated stabilization of α-hemoglobin
AU - Feng, Liang
AU - Gell, David A.
AU - Zhou, Suiping
AU - Gu, Lichuan
AU - Kong, Yi
AU - Li, Jianqing
AU - Hu, Min
AU - Yan, Nieng
AU - Lee, Christopher
AU - Rich, Anne M.
AU - Armstrong, Robert S.
AU - Lay, Peter A.
AU - Gow, Andrew J.
AU - Weiss, Mitchell J.
AU - MacKay, Joel P.
AU - Shi, Yigong
PY - 2004/11/24
Y1 - 2004/11/24
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2004.11.025
DO - 10.1016/j.cell.2004.11.025
M3 - Article
C2 - 15550245
AN - SCOPUS:8844285199
VL - 119
SP - 629
EP - 640
JO - Cell
JF - Cell
SN - 0092-8674
IS - 5
ER -