Structural basis for nutrient acquisition by dominant members of the gut microbiota

大肠被极其密集的细菌种群定植，统称为结肠微生物区系。最近的研究表明，微生物区系在维持正常健康和营养方面发挥着重要作用。微生物区系的失衡与从自身免疫性疾病到癌症和肥胖症等一系列疾病有关。微生物区系的功能和组成取决于单个微生物在人类大肠竞争激烈的环境中获取淀粉和其他膳食多糖等营养物质的能力。这一营养获取过程是由嵌入细菌细胞膜的蛋白质机器完成的。在许多微生物组成员中，这个机器是一个由底物结合蛋白(称为SusD)和通道形成运输蛋白(称为SusC)组成的双组分复合体。我们用X-射线结晶学测定了一个SusCD络合物的首次三维原子结构，并为另一个SusCD络合物获得了高质量的晶体。这些令人兴奋的初步数据构成了这一提议的基础，在这一提议中，我们将详细阐明这些SusCD复合体是如何将其底物运输到细菌细胞中的。通过回答一些“这是怎么发生的？”问题，我们的项目将提供对微生物区系功能的基本见解，并了解人与微生物区系的共生。重要的是，这样的结果将是对目前大多数微生物区系研究的及时和必要的补充，目前的微生物区系研究侧重于回答诸如“谁在那里，何时在那里？”等问题。通过将机械学和系统生物学联系起来，我们的项目也可能具有实际意义，通过干扰关键的养分吸收过程来提供操纵微生物区系组成的见解。

The large bowel is colonised by an extremely dense population of bacteria, collectively termed the colonic microbiota. Recent research indicates that the microbiota play an important role in maintaining normal health and nutrition. Imbalances in the microbiota have been linked to a wide range of diseases from autoimmune disease to cancer and obesity. The function and composition of the microbiota is dependent on the ability of individual micro-organisms to acquire nutrients such as starch and other dietary polysaccharides in the highly competitive environment of the human large bowel. This process of nutrient acquisition is carried out by protein machines embedded in the bacterial cell envelope. In many microbiota members, this machine is a two-component complex consisting of a substrate binding protein (termed SusD) and a channel-forming transport protein (termed SusC). We have determined the first three-dimensional atomic structure of a SusCD complex by X-ray crystallography and have obtained good-quality crystals for another SusCD complex. These exciting preliminary data form the basis of this proposal, in which we will elucidate in detail how these SusCD complexes transport their substrates into the bacterial cell. By answering a number of "how does it happen?" questions, our project will provide fundamental insights into the functioning of the microbiota and understanding the human-microbiota symbiosis. Importantly, such results will be a timely and necessary complement to most current microbiota research, which is focused on answering questions such as "who is there and when?". By linking mechanistic and systems biology, our project could also have practical implications by providing insights to manipulate the composition of the microbiota via interference with critical nutrient uptake processes.