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Lpp positions peptidoglycan at the AcrA-TolC interface in the AcrAB-TolC multidrug efflux pump
Biophysical Journal ( IF 3.4 ) Pub Date : 2021-08-17 , DOI: 10.1016/j.bpj.2021.08.016
James C Gumbart 1 , Josie L Ferreira 2 , Hyea Hwang 3 , Anthony J Hazel 1 , Connor J Cooper 4 , Jerry M Parks 4 , Jeremy C Smith 5 , Helen I Zgurskaya 6 , Morgan Beeby 2
Affiliation  

The multidrug efflux pumps of Gram-negative bacteria are a class of complexes that span the periplasm, coupling both the inner and outer membranes to expel toxic molecules. The best-characterized example of these tripartite pumps is the AcrAB-TolC complex of Escherichia coli. However, how the complex interacts with the peptidoglycan (PG) cell wall, which is anchored to the outer membrane (OM) by Braun’s lipoprotein (Lpp), is still largely unknown. In this work, we present molecular dynamics simulations of a complete, atomistic model of the AcrAB-TolC complex with the inner membrane, OM, and PG layers all present. We find that the PG localizes to the junction of AcrA and TolC, in agreement with recent cryo-tomography data. Free-energy calculations reveal that the positioning of PG is determined by the length and conformation of multiple Lpp copies anchoring it to the OM. The distance between the PG and OM measured in cryo-electron microscopy images of wild-type E. coli also agrees with the simulation-derived spacing. Sequence analysis of AcrA suggests a conserved role for interactions with PG in the assembly and stabilization of efflux pumps, one that may extend to other trans-envelope complexes as well.



中文翻译:

Lpp 将肽聚糖定位在 AcrAB-TolC 多药外排泵的 AcrA-TolC 界面

革兰氏阴性菌的多药外排泵是一类跨越周质的复合物,将内膜和外膜耦合以排出有毒分子。这些三联泵最典型的例子是大肠杆菌的 AcrAB-TolC 复合物. 然而,该复合物如何与通过布劳恩脂蛋白 (Lpp) 锚定在外膜 (OM) 上的肽聚糖 (PG) 细胞壁相互作用,在很大程度上仍是未知的。在这项工作中,我们展示了具有内膜、OM 和 PG 层的 AcrAB-TolC 复合物的完整原子模型的分子动力学模拟。我们发现 PG 定位于 AcrA 和 TolC 的交界处,与最近的冷冻断层扫描数据一致。自由能计算表明,PG 的定位取决于多个 Lpp 拷贝的长度和构象,这些拷贝将其锚定到 OM。在野生型大肠杆菌的低温电子显微镜图像中测量的 PG 和 OM 之间的距离也与模拟衍生的间距一致。AcrA 的序列分析表明与 PG 的相互作用在外排泵的组装和稳定中具有保守的作用,这种作用也可能扩展到其他包膜复合物。

更新日期:2021-09-21
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