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The two redox states of the human NEET proteins’ [2Fe–2S] clusters
JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2021-08-28 , DOI: 10.1007/s00775-021-01890-8
Ke Zuo 1, 2 , Henri-Baptiste Marjault 1, 2 , Kara L Bren 3 , Giulia Rossetti 4, 5, 6 , Rachel Nechushtai 1 , Paolo Carloni 2, 4, 7
Affiliation  

The NEET proteins constitute a unique class of [2Fe–2S] proteins. The metal ions bind to three cysteines and one histidine. The proteins’ clusters exist in two redox states; the oxidized protein (containing two FeIII ions) can transfer the cluster to apo-acceptor protein(s), while the reduced form (containing one ferrous ion) remains bound to the protein frame. Here, we perform in silico and in vitro studies on human NEET proteins in both reduced and oxidized forms. Quantum chemical calculations on all available human NEET proteins structures suggest that reducing the cluster weakens the Fe–NHis and Fe–SCys bonds, similar to what is seen in other Fe–S proteins (e.g., ferredoxin and Rieske protein). We further show that the extra electron in the [2Fe–2S]+ clusters of one of the NEET proteins (mNT) is localized on the His-bound iron ion, consistently with our previous spectroscopic studies. Kinetic measurements demonstrate that the mNT [2Fe–2S]+ is released only by an increase in temperature. Thus, the reduced state of human NEET proteins [2Fe–2S] cluster is kinetically inert. This previously unrecognized kinetic inertness of the reduced state, along with the reactivity of the oxidized state, is unique across all [2Fe–2S] proteins. Finally, using a coevolutionary analysis, along with molecular dynamics simulations, we provide insight on the observed allostery between the loop L2 and the cluster region. Specifically, we show that W75, R76, K78, K79, F82 and G85 in the latter region share similar allosteric characteristics in both redox states.

Graphic abstract



中文翻译:


人类 NEET 蛋白 [2Fe–2S] 簇的两种氧化还原态



NEET 蛋白构成了一类独特的 [2Fe–2S] 蛋白。金属离子与三个半胱氨酸和一个组氨酸结合。蛋白质簇以两种氧化还原状态存在;氧化的蛋白质(含有两个 Fe III离子)可以将簇转移到脱辅基受体蛋白质上,而还原形式(含有一个亚铁离子)仍然与蛋白质框架结合。在这里,我们对还原和氧化形式的人类 NEET 蛋白进行计算机和体外研究。对所有可用的人类 NEET 蛋白结构的量子化学计算表明,减少簇会削弱 Fe-N His和 Fe-S Cys键,类似于其他 Fe-S 蛋白(例如铁氧还蛋白和 Rieske 蛋白)中所见的情况。我们进一步表明,NEET 蛋白(mNT)之一的 [2Fe–2S] +簇中的额外电子位于与 His 结合的铁离子上,这与我们之前的光谱研究一致。动力学测量表明 mNT [2Fe–2S] +仅通过温度升高而释放。因此,人类 NEET 蛋白 [2Fe-2S] 簇的还原态在动力学上是惰性的。这种以前未被认识到的还原态动力学惰性以及氧化态的反应性在所有 [2Fe-2S] 蛋白质中都是独一无二的。最后,利用协同进化分析以及分子动力学模拟,我们深入了解了环 L2 和簇区域之间观察到的变构。具体来说,我们表明后一个区域中的 W75、R76、K78、K79、F82 和 G85 在两种氧化还原态下具有相似的变构特征。

 图文摘要

更新日期:2021-08-29
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