Controlling the Elongasome: Exploring protein complex formation in the bacterial protein complex responsible for cell shape.

细胞形状的决定及其与细胞分裂的关系是生物学中的一个基本问题。在细菌中，这一过程的主要组成部分是由必需的细胞外聚合物肽聚糖（PG）提供的，PG是围绕细胞质膜的网状小囊，由聚合的聚糖链组成，由短肽交联。破坏PG生物合成导致细胞裂解或停止生长，使其成为抗生素的主要靶点。这是许多天然产物抗生素以及半合成药物（包括迄今为止临床上最成功的抗生素-内酰胺类药物）的致命弱点。虽然从基础生物学和转化医学的角度广泛认识到这些因素，但导致PG形成的事件的协调仍然是一个知识严重缺乏的领域，特别是在分子水平上的细节。参与PG合成的蛋白质，从合成前体脂质II的细胞质酶到负责其聚合的胞外酶，已经分别进行了生化和结构表征。然而，越来越多的证据表明，许多（如果不是大多数的话）这些酶在体内作为多蛋白复合物“机器”的一部分起作用，促进快速有效的PG合成。在这个项目中，我们将专注于一组被统称为长体的蛋白质，它们负责决定细胞形状。根据结构和生物信息学信息，我们正在研究这种蛋白质复合物的组装方式，并影响长体在细菌中组装肽聚糖层的方式。该项目的目标是在分子水平上理解这种生物合成复合物的组织如何促进最佳途径功能，从而促进细胞形状和生长。

The determination of cell shape and its relationship to cell division is a fundamental question in biology. In bacteria, a major component of this process is provided by the essential extracellular polymer peptidoglycan (PG), which is a mesh-like sacculus surrounding the cytoplasmic membrane and is composed of polymerized glycan chains, cross-linked by short peptides. Disruption of PG biosynthesis results in cell lysis or cessation of growth, making it a major target for antibiotics. This is exploited as an Achilles's heel by many natural product antibiotics as well semisynthetic drugs including the beta-lactams, the most clinically successful antibiotics to date. Whilst there is wide recognition of these factors from a basic biology and translational medicine perspective, the coordination of the events that lead to the formation of PG remains an area where knowledge is critically lacking, particularly at a molecular level of detail. The proteins that participate in PG synthesis, from the cytoplasmic enzymes that synthesize the precursor Lipid II to the extracellular enzymes that are responsible for its polymerisation, have been individually characterized biochemically and structurally. However, increasing evidence suggests that many if not most of these enzymes function in vivo as part of a multi-protein complex "machine" which facilitates rapid and efficient PG synthesis. In this project we will be focusing on a subset of proteins collectively termed the elongasome that are responsible for the determination of cell shape. Informed by structural and bioinformatic information, we are examining the way in which this protein complex assembles and affects the way in which the elongasome assembles the peptidoglycan layer in bacteria. The goal of this project is to understand at a molecular level how the organization of this biosynthetic complex facilitates optimal pathway function and thus cell shape and growth.