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

我们的建议侧重于在鲍曼不动杆菌毒株中发现的六种bcct的协同分子调控机制。我们假设它们与机械敏感通道一起受到膜物理状态变化的调节，例如曲率，膜张力或膜的脂质组成，并且这种脂质调节通过特定的脂质物种将它们与毒力联系起来。我们将研究这些BCC膜转运蛋白和机械敏感通道的结构和功能及其协同调控。此外，我们的目标是破译哪些脂质物种调节bcct和MS通道的转录和活性。此外，我们将研究这组膜蛋白是否与内外膜之间的囊泡运输有关。综上所述，我们希望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。我们小组将使用整个结构生物学工具箱，包括x射线晶体学、低温电镜单粒子分析和低温电镜断层扫描、单分子FRET显微镜和HDX光谱。

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.