Molecular mechanism of AHSP-mediated stabilization of α-hemoglobin
Molecular mechanism of AHSP-mediated stabilization of α-hemoglobin
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DOI：
10.1016/j.cell.2004.11.025
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发表时间：
2004-11-24
期刊：
影响因子：
64.5
通讯作者：
Shi, YG
中科院分区：
文献类型：
--
作者：
Feng, L;Gell, DA;Shi, YG
人类体内的氧气输送系统--血红蛋白A(HBA)由两个a亚基和两个β亚基组成。游离α-血红蛋白(α-Hb)是不稳定的，其沉淀参与了β-地中海贫血的病理生理过程。在红细胞中，α-血红蛋白稳定蛋白(AHSP)结合AFT并抑制其沉淀。与Fe(II)-αHb结合的AHSP的晶体结构表明，AHSP通过一个疏水界面特异性识别αHb的G和H螺旋，该界面在很大程度上概括了血红蛋白的α(1)-β(1)界面。AHSP-AlphaHb的相互作用是广泛的，但不是最优的，这解释了为什么β-血红蛋白可以竞争性地取代AHSP形成HBA。值得注意的是，与AFT结合的AHSP中的Fe(II)-血红素基团由远端的组氨酸协调，而不是近端的组氨酸。重要的是，与AHSP的结合有助于氧-αHb转化为脱氧、氧化的[Fe(III)]非反应形式，其中所有六个配位都被占据。这些观察揭示了AHSP稳定游离αHb的分子机制。
Hemoglobin A (HbA), the oxygen delivery system in humans, comprises two a and two beta subunits. Free alpha-hemoglobin (alphaHb) is unstable, and its precipitation contributes to the pathophysiology of beta thalassemia. In erythrocytes, the alpha-hemoglobin stabilizing protein (AHSP) binds aft and inhibits its precipitation. The crystal structure of AHSP bound to Fe(II)-alphaHb reveals that AHSP specifically recognizes the G and H helices of alphaHb through a hydrophobic interface that largely recapitulates the alpha(1)-beta(1) interface of hemoglobin. The AHSP-alphaHb interactions are extensive but suboptimal, explaining why beta-hemoglobin can competitively displace AHSP to form HbA. Remarkably, the Fe(II)-heme group in AHSP bound aft is coordinated by the distal but not the proximal histidine. Importantly, binding to AHSP facilitates the conversion of oxy-alphaHb 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 alphaHb.