King's College London, UK.
UK Dementia Research Institute at King's College London, UK.
FEBS J. 2019 Feb;286(3):495-506. doi: 10.1111/febs.14750. Epub 2019 Jan 30.
Frataxins form an interesting family of iron-binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron-sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, we discuss the X-ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. We show that this eukaryotic frataxin has an unusual variation in the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable among the frataxin orthologues. We also characterized the iron-binding mode of Ct frataxin and demonstrated that it binds it through a semiconserved negatively charged ridge on the first helix and beta-strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron-sulfur cluster synthesis, and act as its inhibitor.
铁载体蛋白形成了一个有趣的家族，它们具有几乎独特的折叠结构，在从细菌到灵长类动物的范围内高度保守。它们在铁硫簇生物发生中起着关键作用，作为簇形成速率的调节剂，这是由以下事实证明的：铁载体蛋白的缺失与生命不相容，并且蛋白质水平降低会导致隐性神经退行性疾病弗里德里希共济失调。尽管它很重要，但铁载体蛋白的结构仅从相对较少的物种中得到解决。在这里，我们讨论了嗜热真菌 Chaetomium thermophilum 中的铁载体蛋白的 X 射线结构，以及其在溶液中的相互作用和动力学特性的表征。我们表明，这种真核铁载体蛋白在经典铁载体蛋白折叠中具有不寻常的变化：最后一个螺旋比其他铁载体蛋白短，导致结构不太对称和紧凑。该蛋白质的稳定性可与人类铁载体蛋白相媲美，目前是铁载体蛋白同源物中最稳定的。我们还对 Ct 铁载体蛋白的铁结合模式进行了表征，并证明它通过第一个螺旋和β链上的半保守负电荷脊结合铁。此外，这种铁载体蛋白还能够结合细菌脱硫酶的同源物，该同源物在铁硫簇合成中起中心作用，并作为其抑制剂。
