Structural bases for the interaction of frataxin with the central components of iron-sulphur cluster assembly.
Structural bases for the interaction of frataxin with the central components of iron-sulphur cluster assembly.
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DOI：
10.1038/ncomms1097
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发表时间：
2010-10-19
影响因子：
16.6
通讯作者：
Pastore, Annalisa
中科院分区：
文献类型：
--
作者：
Prischi, Filippo;Konarev, Petr V.;Iannuzzi, Clara;Pastore, Chiara;Adinolfi, Salvatore;Martin, Stephen R.;Svergun, Dmitri I.;Pastore, Annalisa
Frataxin是一种功能尚不清楚的重要蛋白质，其水平降低是导致神经退行性病变Friedreich‘s共济失调的原因。独立报告通过与这一机制的两个核心组成部分：脱硫酶Nfs1/Iscs和支架蛋白ISU/Iscu的相互作用，将Frataxin与铁-硫簇组装联系起来。在这项研究中，我们使用生物物理方法的组合来确定CyaY(Frataxin的细菌同源物)与ISCS/ISCU复合体相互作用的结构基础。我们发现CyaY以单体的形式结合在活性中心和ISCS二聚体界面之间的口袋中。识别不需要铁，通过互补带电残基的静电相互作用发生。复合界面上的突变会影响酶簇的形成速度。CyaY结合增强了ISCS/ISCU复合体的亲和力。我们的数据为理解Frataxin作为ISCS功能调节因子的作用提供了一个新的范式。Frataxin是一种与铁-硫簇组装有关的重要蛋白质，水平降低与Friedrich‘s共济失调有关。在这项研究中，使用了多种技术相结合的方法来探索细菌Frataxin同源物CyaY与铁-硫簇组装机器的相互作用。
Reduced levels of frataxin, an essential protein of as yet unknown function, are responsible for causing the neurodegenerative pathology Friedreich's ataxia. Independent reports have linked frataxin to iron–sulphur cluster assembly through interactions with the two central components of this machinery: desulphurase Nfs1/IscS and the scaffold protein Isu/IscU. In this study, we use a combination of biophysical methods to define the structural bases of the interaction of CyaY (the bacterial orthologue of frataxin) with the IscS/IscU complex. We show that CyaY binds IscS as a monomer in a pocket between the active site and the IscS dimer interface. Recognition does not require iron and occurs through electrostatic interactions of complementary charged residues. Mutations at the complex interface affect the rates of enzymatic cluster formation. CyaY binding strengthens the affinity of the IscS/IscU complex. Our data suggest a new paradigm for understanding the role of frataxin as a regulator of IscS functions. Frataxin is an essential protein that has been linked to iron–sulphur cluster assembly, and reduced levels are associated with Friedrich's ataxia. In this study, a combination of techniques is used to probe the interactions of the bacterial frataxin orthologue CyaY with the iron–sulphur cluster assembly machinery.
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