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The ABC exporter IrtAB imports and reduces mycobacterial siderophores

机译：ABC出口商IrtAB进口并减少分枝杆菌铁载体

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摘要

Intracellular replication of the deadly pathogen Mycobacterium tuberculosis relies on the production of small organic molecules called siderophores that scavenge iron from host proteins(1). M. tuberculosis produces two classes of siderophore, lipid-bound mycobactin and water-soluble carboxymycobactin(2,3). Functional studies have revealed that iron-loaded carboxymycobactin is imported into the cytoplasm by the ATP binding cassette (ABC) transporter IrtAB(4), which features an additional cytoplasmic siderophore interaction domain(5). However, the predicted ABC exporter fold of IrtAB is seemingly contradictory to its import function. Here we show that membrane-reconstituted IrtAB is sufficient to import mycobactins, which are then reduced by the siderophore interaction domain to facilitate iron release. Structure determination by X-ray crystallography and cryo-electron microscopy not only confirms that IrtAB has an ABC exporter fold, but also reveals structural peculiarities at the transmembrane region of IrtAB that result in a partially collapsed inward-facing substrate-binding cavity. The siderophore interaction domain is positioned in close proximity to the inner membrane leaflet, enabling the reduction of membrane-inserted mycobactin. Enzymatic ATPase activity and in vivo growth assays show that IrtAB has a preference for mycobactin over carboxymycobactin as its substrate. Our study provides insights into an unusual ABC exporter that evolved as highly specialized siderophore-import machinery in mycobacteria.
机译：致命病原体结核分枝杆菌的细胞内复制依赖于称为铁载体的小有机分子的产生，该分子从宿主蛋白中清除铁（1）。结核分枝杆菌产生两类铁载体，脂质结合型霉菌素和水溶性羧基霉菌素（2,3）。功能研究表明，铁结合的羧分枝杆菌素是通过ATP结合盒（ABC）转运蛋白IrtAB（4）导入细胞质的，后者具有额外的细胞质铁载体相互作用结构域（5）。但是，预期的IrtAB的ABC出口商折叠似乎与它的进口功能矛盾。在这里，我们显示膜重建的IrtAB足以导入分枝杆菌素，然后通过铁载体相互作用域将其还原以促进铁释放。通过X射线晶体学和低温电子显微镜确定结构，不仅证实IrtAB具有ABC出口折叠，而且还揭示了IrtAB跨膜区域的结构特征，导致部分向内的底物结合腔塌陷。铁载体相互作用结构域紧邻内膜小叶，从而减少了插入膜的霉菌素。酶促ATPase活性和体内生长试验表明，IrtAB比支链霉菌素更倾向于支链霉菌素。我们的研究提供了对一个不寻常的ABC出口商的见解，该出口商在分枝杆菌中演变成高度专业化的铁载体导入机械。

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  • 来源
    《Nature》 |2020年第7803期|413-417|共5页
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    Univ Zurich Inst Med Microbiol Zurich Switzerland;

    Univ Zurich Dept Biochem Zurich Switzerland;

    Univ Texas Dallas Dept Chem & Biochem Richardson TX 75083 USA;

    Univ Zurich Inst Med Microbiol Zurich Switzerland|Linkster Therapeut Zurich Switzerland;

    Swiss Fed Inst Technol Inst Microbiol Zurich Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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