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

细胞形状的确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，该过程的主要组分由必需的细胞外聚合物肽聚糖（PG）提供，肽聚糖（PG）是围绕细胞质膜的网状球囊，并且由聚合的聚糖链组成，通过短肽交联。PG生物合成的破坏导致细胞裂解或生长停止，使其成为抗生素的主要靶标。这被许多天然产物抗生素以及半合成药物（包括β-内酰胺类，迄今为止临床上最成功的抗生素）用作阿喀琉斯之踵。虽然从基础生物学和转化医学的角度对这些因素有广泛的认识，但导致PG形成的事件的协调仍然是一个严重缺乏知识的领域，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细胞外酶，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，这些酶中的许多（如果不是大多数的话）在体内作为多蛋白质复合物“机器”的一部分起作用，其促进快速和有效的PG合成。在这个项目中，我们将集中在一个子集的蛋白质统称为长体，负责决定细胞的形状。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组装的方式，并影响延长酶体组装细菌中肽聚糖层的方式。该项目的目标是在分子水平上了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.