Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 629-640 |
| Number of pages | 12 |
| Journal | Cell |
| Volume | 119 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 24 Nov 2004 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
Molecular mechanism of AHSP-mediated stabilization of α-hemoglobin. / Feng, Liang; Gell, David A.; Zhou, Suiping; Gu, Lichuan; Kong, Yi; Li, Jianqing; Hu, Min; Yan, Nieng; Lee, Christopher; Rich, Anne M.; Armstrong, Robert S.; Lay, Peter A.; Gow, Andrew J.; Weiss, Mitchell J.; MacKay, Joel P.; Shi, Yigong.
In: Cell, Vol. 119, No. 5, 24.11.2004, p. 629-640.Research output: Contribution to journal › Article
}
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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UR - http://www.scopus.com/inward/citedby.url?scp=8844285199&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2004.11.025
DO - 10.1016/j.cell.2004.11.025
M3 - Article
VL - 119
SP - 629
EP - 640
JO - Cell
JF - Cell
SN - 0092-8674
IS - 5
ER -