Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
Structure. 2020 Jun 2;28(6):625-634.e6. doi: 10.1016/j.str.2020.03.013. Epub 2020 Apr 28.
The small protein AcrZ in Escherichia coli interacts with the transmembrane portion of the multidrug efflux pump AcrB and increases resistance of the bacterium to a subset of the antibiotic substrates of that transporter. It is not clear how the physical association of the two proteins selectively changes activity of the pump for defined substrates. Here, we report cryo-EM structures of AcrB and the AcrBZ complex in lipid environments, and comparisons suggest that conformational changes occur in the drug-binding pocket as a result of AcrZ binding. Simulations indicate that cardiolipin preferentially interacts with the AcrBZ complex, due to increased contact surface, and we observe that chloramphenicol sensitivity of bacteria lacking AcrZ is exacerbated when combined with cardiolipin deficiency. Taken together, the data suggest that AcrZ and lipid cooperate to allosterically modulate AcrB activity. This mode of regulation by a small protein and lipid may occur for other membrane proteins.
大肠杆菌中的小蛋白 AcrZ 与多药外排泵 AcrB 的跨膜部分相互作用，增加了细菌对该转运蛋白的一部分抗生素底物的抗性。目前尚不清楚这两种蛋白质的物理结合如何选择性地改变泵对特定底物的活性。在这里，我们报告了在脂质环境中 AcrB 和 AcrBZ 复合物的冷冻电镜结构，比较表明，由于 AcrZ 的结合，药物结合口袋中发生构象变化。模拟表明，由于接触面积增加，心磷脂优先与 AcrBZ 复合物相互作用，我们观察到缺乏 AcrZ 的细菌对氯霉素的敏感性在与心磷脂缺乏结合时加剧。总之，数据表明 AcrZ 和脂质协同作用，别构调节 AcrB 的活性。这种由小蛋白和脂质调节的模式可能发生在其他膜蛋白中。
