Understanding Movement and Mechanism in essential Mammalian Membrane Transporters

我们研究膜蛋白的结构和功能动力学，许多与医学相关。特别感兴趣的是包括超复合体在内的大的多亚单位复合体以及转运蛋白系统及其与细胞内信号通路的相互作用。越来越多的证据表明，膜蛋白并不是单独作用的，而是作为纳米机器组织起来的，这些纳米机器通过其各个组件的协同作用发挥作用，在时间和空间上都观察到了高精度和特异性。我们正在寻求解开这些蛋白质纳米机器的结构和动力学以及它们的功能和调节的基本原理。我们的实验方法侧重于使用磁共振波谱，特别是电子顺磁共振(EPR)和核磁共振(核磁共振)技术，并结合分子生物学和生化方法。此外，先进的分子动力学技术(MD)被用来支持实验观察，以提供对功能的动态描述。该项目通过研究一种特定的细菌天冬氨酸转运蛋白来增加这一重要的跨生物膜转运主题，该转运蛋白是哺乳动物谷氨酸转运蛋白的古代同源物，与包括癫痫和阿尔茨海默病在内的各种神经疾病有关。最近的静态晶体结构表明了大规模的构象变化，我们的目标是结合最先进的磁共振技术和分子动力学模拟来探索蛋白质功能的功能动力学。

We study the architecture and functional dynamics of membrane proteins, many medically relevant. Special interest is on large multi-subunit complexes including supercomplexes as well as on transporter systems and their interaction with intra-cellular signalling pathways. There is increasing evidence that membrane proteins do not act alone, but that they are organised as nano-machineries which function through the concerted action of its individual components with high precision and specificity observed in both time and space. We are seeking to unravel the principles underlying the architecture and dynamics of these protein nano-machineries as well as their function and regulation. Our experimental approach focuses on the use of magnetic resonance spectroscopy specifically electron paramagnetic resonance (EPR) and Nuclear Magnetic Resonance (NMR) techniques in combination with molecular biological, and biochemical approaches. In addition advanced molecular dynamics techniques (MD) are used to underpin the experimental observations to provide a dynamic description of function. This project addesses this important theme of transport across biological membrane through the study of a specific bacterial aspartate transporter which is an archaeal homolog of mammalian glutamate transporters, implicated in various neurological diseases including epilepsy and Alzheimer's disease. Recent static crystal structures have suggested large scale conformational changes and we aim to probe the functional dynamics of the protein function using a combination of state-of-the-art magnetic resonance techniques and molecular dynamics simulations.