Structural basis of lipoprotein recognition by the bacterial Lol trafficking chaperone LolA.
Structural basis of lipoprotein recognition by the bacterial Lol trafficking chaperone LolA.
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DOI：
10.1073/pnas.2208662119
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发表时间：
2022-09-06
影响因子：
11.1
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中科院分区：
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革兰氏阴性菌中的脂蛋白支持外膜的形成和维持，外膜构成对抗抗生素和其他有害分子的重要保护屏障。需要一个包含LolABCDE蛋白的基本转运系统将脂蛋白转运至外膜。在内膜上成熟并被LolCDE转运蛋白提取后，脂蛋白被传递到伴侣LolA，该伴侣LolA在通过LolB受体插入外膜之前携带它们穿过周质。在这里，我们报告的分子细节的脂蛋白相互作用的伴侣LolA，一个关键的中间体位于心脏的Lol途径。该结构为这一重要系统提供了有价值的见解，并可用于开发新的抗菌剂。在革兰氏阴性细菌中，脂蛋白是外膜（OM）的重要结构成分，也是细胞包膜生理学的关键机制。一个专用的装置，Lol系统，是正确定位OM脂蛋白所必需的，对生存力至关重要。周质伴侣LolA是该运输途径的中心，在将三酰化脂蛋白携带穿过周质到达OM受体LolB之前，从内膜转运蛋白LolCDE接受三酰化脂蛋白。在这里，我们报告了晶体结构的配体LolA，在体内产生的，揭示了脂蛋白协会的分子细节。该结构突出了LolA如何通过与LolC的相互作用而初始地接受脂蛋白，进一步打开以在其腔内以精确的构象容纳三个配体酰基链。LolA与酰基链形成广泛的相互作用，但不与货物的任何残基相互作用，这解释了伴侣转运结构多样的脂蛋白的能力。不能释放脂蛋白的ligandedLolA变体的结构表征揭示了异常的关联，证明了LolA的LolCDE协调的顺序打开对于以生产性的方式插入脂蛋白以用于随后的运输的重要性。与LolA与LolC或LolCDE复合的现有结构的比较揭示了LolA腔内脂蛋白和LolC结合位点的实质性重叠，表明脂蛋白酰基链的插入通过干扰与LolC的相互作用而使伴侣蛋白从转运蛋白物理上脱离。总而言之，我们的数据为全面了解至关重要的贩运途径迈出了关键一步。
Lipoproteins in gram-negative bacteria underpin the formation and maintenance of the outer membrane that constitutes a vital protective barrier against antibiotics and other noxious molecules. An essential transport system comprising the LolABCDE proteins is required to traffic lipoproteins to the outer membrane. Following maturation on the inner membrane and extraction by the LolCDE transporter, lipoproteins are passed to the chaperone LolA that carries them across the periplasm prior to insertion into the outer membrane by the LolB receptor. Here, we report the molecular details of lipoprotein interaction with the chaperone LolA, a key intermediate located at the heart of the Lol pathway. The structure provides valuable insights into this important system and could be exploited to develop new antimicrobials. In gram-negative bacteria, lipoproteins are vital structural components of the outer membrane (OM) and crucial elements of machineries central to the physiology of the cell envelope. A dedicated apparatus, the Lol system, is required for the correct localization of OM lipoproteins and is essential for viability. The periplasmic chaperone LolA is central to this trafficking pathway, accepting triacylated lipoproteins from the inner membrane transporter LolCDE, before carrying them across the periplasm to the OM receptor LolB. Here, we report a crystal structure of liganded LolA, generated in vivo, revealing the molecular details of lipoprotein association. The structure highlights how LolA, initially primed to receive lipoprotein by interaction with LolC, further opens to accommodate the three ligand acyl chains in a precise conformation within its cavity. LolA forms extensive interactions with the acyl chains but not with any residue of the cargo, explaining the chaperone’s ability to transport structurally diverse lipoproteins. Structural characterization of a ligandedLolA variant incapable of lipoprotein release reveals aberrant association, demonstrating the importance of the LolCDE-coordinated, sequential opening of LolA for inserting lipoprotein in a manner productive for subsequent trafficking. Comparison with existing structures of LolA in complex with LolC or LolCDE reveals substantial overlap of the lipoprotein and LolC binding sites within the LolA cavity, demonstrating that insertion of lipoprotein acyl chains physically disengages the chaperone protein from the transporter by perturbing interaction with LolC. Taken together, our data provide a key step toward a complete understanding of a fundamentally important trafficking pathway.
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影响因子：
10.5
作者：
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Hassabis D
影响因子：
2.7
作者：
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通讯作者：
Brown, Eric D.
DOI：
10.1073/pnas.1702248114
发表时间：
2017-05-02
影响因子：
11.1
作者：
Grabowicz, Marcin;Silhavy, Thomas J.
通讯作者：
Silhavy, Thomas J.