ABC exporter function within their lipid microenvironment (P27)

ATP结合盒（ABC）出口商是出现多药耐药的重要贡献者。它们与周围的脂质形成一个微区室，这种微环境的组成直接影响它们的构象谱，以及它们的转运效率。这一现象的分子原因仍然未知，因为全面的比较研究，概括微区室的蛋白质-脂质组成是具有挑战性的。使用cryo-EM，我们最近描述了异二聚体ABC转运蛋白TmrAB在脂质环境中的构象谱，并能够解决多个长期存在的争议。通过这个项目，我们将系统地描述微区室组成对同源二聚体ABC输出者动力学的影响。我们将研究转运蛋白如何启动与底物的结合，并从结构上确定其在不同疏水环境中的构象。我们期望我们的研究将对ABC转运蛋白生物学和膜蛋白的构象动力学产生深远的影响。本计画将增加高解析度的微区室观察角度，并将低温电镜的方法贡献给研究中心。

ATP binding cassette (ABC) exporters are essential contributors to the emergence of multidrugresistance. They form a microcompartment with their surrounding lipids, and the compositionof this microenvironment directly affects their conformational spectrum, as well as theirtransport efficiency. The molecular causes of this remain unknown, as thorough comparativestudies, recapitulating the protein-lipid composition of the microcompartment are challenging.Using cryo-EM, we have recently described the conformational spectrum of the heterodimericABC transporter TmrAB in a lipid environment and were able to address multiple long-standingcontroversies. With this project, we will systematically characterize the impact ofmicrocompartment composition on the dynamics of a homodimeric ABC exporter. We willinvestigate how the transporter initiates binding to a substrate and structurally determine itsconformations in different hydrophobic environments. We expect that our research will havefar-reaching implications in ABC transporter biology and of conformational dynamics ofmembrane proteins in general. This project will add a high-resolution angle to the descriptionof microcompartments and will contribute the method of cryo-EM to the research center.