小柯机器人

IrtAB介导分枝杆菌铁载体的转入和还原
2020-03-29 23:45

瑞士苏黎世大学Markus A. Seeger研究组的一项最新研究结果显示,ATP结合盒(ABC)IrtAB出口介导分枝杆菌铁载体的转入和还原。这一研究成果在线发表在2020年3月25日出版的国际学术期刊《自然》上。

在这项研究中,研究人员发现膜重构的IrtAB足以转运分枝杆菌素,然后通过铁载体相互作用结构域将其还原以促进铁释放。通过X衍射晶体学和冷冻电镜确定其结构,研究人员不仅证实IrtAB具有ABC出口-折叠,而且还揭示了IrtAB跨膜结构域的结构特性,其导致向内底物结合腔部分塌陷。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活性和体内生长实验表明与羧化霉菌素相比,IrtAB更偏爱分枝杆菌素。该研究提供了对非典型ABC出口的见解,该出口在分枝杆菌中已发展成为高度专业化的铁载体转入通道。

据了解,致命病原体结核分枝杆菌的胞内复制依赖于名为铁载体有机小分子的产生,这些分子从宿主蛋白中清除铁。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。功能研究表明,铁结合的羧基分枝杆菌素是通过ABC转运蛋白IrtAB4转入细胞质的,后者具有额外的细胞质铁载体相互作用结构域。但是, IrtAB的预测ABC出口-折叠功能似乎与它的进口功能相矛盾。

附:英文原文

Title: The ABC exporter IrtAB imports and reduces mycobacterial siderophores

Author: Fabian M. Arnold, Miriam S. Weber, Imre Gonda, Marc J. Gallenito, Sophia Adenau, Pascal Egloff, Iwan Zimmermann, Cedric A. J. Hutter, Lea M. Hrlimann, Eike E. Peters, Jrn Piel, Gabriele Meloni, Ohad Medalia, Markus A. Seeger

Issue&Volume: 2020-03-25

Abstract: Intracellular replication of the deadly pathogen Mycobacterium tuberculosis relies on the production of small organic molecules called siderophores that scavenge iron from host proteins1. M. tuberculosis produces two classes of siderophore, lipid-bound mycobactin and water-soluble carboxymycobactin2,3. Functional studies have revealed that iron-loaded carboxymycobactin is imported into the cytoplasm by the ATP binding cassette (ABC) transporter IrtAB4, which features an additional cytoplasmic siderophore interaction domain5. 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.

DOI: 10.1038/s41586-020-2136-9

Source: https://www.nature.com/articles/s41586-020-2136-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0