Structural & Biochemical Characterisation of the Streptococcus pneumoniae Early-Stage Division Complex, FtsEX-PcsB.

结构性

• 批准号: 2264827
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2264827
• 关键词: Structural; Biochemical; Characterisation; Streptococcus; pneumoniae

Bacterial cell division is seen as one of the most highly conserved processes that occurs in that kingdom. FtsA (bacterial actin) works to anchor the Z-ring of FtsZ (bacterial tubulin) to the inner side of the cytoplasmic membrane, before other downstream components of the Divisome assemble in a highly coordinated manner. Two of these proteins are the ATPase FtsE, and the polytopic membrane protein FtsX that assemble as part of the early-stage Divisome assembly, which are required for subsequent assembly of further downstream components. Further to this, the FtsEX complex has been implemented in a peptidoglycan (PG) breakdown during daughter cell separation. To facilitate this, FtsX associates with the probable PG hydrolase, PcsB. These interaction as well as the control mechanisms are not well understood, and may provide crucial insight into future chemotherapeutic strategies that will govern the development of next-generation antibiotics. We propose to study this system in the Gram-positive organism, Streptococcus pneumoniae; an opportunistic pathogen responsible for around 6000 deaths per year, predominantly in the elderly and children under 5. Recently, the S. pneumoniae PcsB crystal structure has been solved, revealing a V-shaped conformation, the active site containing CHAPS domain residing close to the coiled-coil domain. Based on the homologous interaction between FtsX and EnvC in E. coli, PcsB will need to undergo a conformational change in order to become activated. This may be facilitated by the ATPase action of FtsE, though the molecular mechanisms are unclear; which is in part what we propose to study in this project.

细菌细胞分裂被认为是该领域发生的最高度保守的过程之一。在分裂体的其他下游组分以高度协调的方式组装之前，FtsA（细菌肌动蛋白）的作用是将FtsZ（细菌微管蛋白）的z环锚定在细胞质膜的内侧。其中两种蛋白质是atp酶富时蛋白和多聚膜蛋白富时蛋白，它们作为早期分裂体组装的一部分进行组装，这是后续下游组件组装所必需的。此外，FtsEX复合物已在子细胞分离过程中实现肽聚糖（PG）分解。为了促进这一点，FtsX与可能的PG水解酶PcsB结合。这些相互作用以及控制机制尚未被很好地理解，并且可能为未来的化疗策略提供重要的见解，这些策略将指导下一代抗生素的发展。我们建议在革兰氏阳性菌肺炎链球菌中研究这一系统；一种机会致病菌，每年造成约6000人死亡，主要是老年人和5岁以下儿童。近年来，肺炎链球菌PcsB的晶体结构得到了解析，显示出v型构象，活性位点含有CHAPS结构域，位于螺旋结构域附近。基于FtsX和EnvC在大肠杆菌中的同源相互作用，PcsB需要经历构象变化才能被激活。这可能是由富时的atp酶作用促成的，尽管分子机制尚不清楚；这也是我们计划在这个项目中研究的部分内容。