Cooperative regulation in Acinetobacter baumannii Betaine-Choline-Carnitine transporters and the role of betaine in membrane vesicle trafficking during infection

我们的建议集中在鲍曼不动杆菌强毒株中发现的六种BCCT的协同分子调控机制上。我们推测，与机械敏感通道一起，它们受到膜物理状态的变化的调节，例如，膜的曲率、膜张力或膜的脂组成，这种脂调节通过特定的脂类将它们与毒力联系起来。我们将研究这些BCC膜转运体和机械敏感通道的结构和功能以及它们之间的协同调节。此外，我们的目的是破译哪些脂类物种调节BCCTs和MS通道的转录和活性。此外，我们还将研究这组膜蛋白是否与内膜和外膜之间的囊泡运输有关。总之，我们想要证明甜菜碱在宿主感染过程中发挥着重要而复杂的作用，这可能会导致新的治疗方法。我们的团队将使用整个结构生物学工具箱，包括X射线结晶学、冷冻EM单颗粒分析和冷冻EM断层扫描以及单分子FRET显微镜和HDX光谱分析。

Our proposal focuses on the concerted molecular regulatory mechanism of the set of six BCCTs found in virulent A. baumannii strains. We postulate that together with mechanosensitive channels they are regulated by changes in the physical state of the membrane, e.g., by curvature, membrane tension or the lipid composition of the membrane, and that this lipid-regulation link them to virulence via specific lipid species. We will investigate the structure and function of these BCC membrane transporters and mechanosensitive channels and their cooperative regulation. Moreover, our aim is to decipher which lipid species regulate transcription and activity of the BCCTs and MS channels. In addition, we will investigate whether this group of membrane proteins can be linked to vesicle transport between inner and outer membrane. In summary, we would like to proof that betaine plays an important and complex role during host infection, which might be lead to new therapeutic approaches. Our group will employ the whole structural biology toolbox of X-ray crystallography, cryo-EM single particle analysis and cryo-EM tomography and single molecule FRET microscopy and HDX spectrometry.