Regulating amyloid formation: structural studies of the secretion and assembly of 'curli' fibres

调节淀粉样蛋白的形成：“curli”纤维分泌和组装的结构研究

• 批准号: G1001664/1
• 负责人: Steve Matthews
• 金额: $ 49.76万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1001664%2F1
• 关键词: Regulating; amyloid; formation; structural; studies

Proteins are important building blocks for cells and organs, as well being important messengers that circulate throughout an organism. Occasionally, cells produce abnormal proteins that have tendency to form fibrous protein aggregates. The mis-folding of proteins and their subsequent accumulation into what are now termed ?amyloids? has a major detrimental effect on the health of a cell. Amyloids are therefore implicated in the causes of numerous human diseases, such as type-2 diabetes mellitus, Alzheimer?s and Parkinson?s. Despite the damaging effects of amyloid deposits, bacteria have devised a way of carefully controlling their formation, such that they are prevented from damaging the cell. Bacteria also utilise these fibrous structures, known as ?curli?, to their advantage, such as promoting biofilms and shielding themselves from extreme environmental changes. The curli assembly and secretion system includes a membrane pore that transports amyloid subunits to the outside of the cell and a number of accessory/chaperone molecules that assist in regulating the process. We propose to study the structures and interactions of the curli assembly and secretion system with a view to understanding its mode of action in atomic detail. Current treatments for amyloid diseases of humans are limited and truly effective remedies have yet to be developed, therefore they represent a major public health concern. Our studies will provide guidance for the rational design of new therapeutic approaches for preventing or treating slowing amyloid diseases in humans.

蛋白质是细胞和器官的重要组成部分，也是在整个生物体中循环的重要信使。偶尔，细胞产生异常蛋白质，这些蛋白质倾向于形成纤维状蛋白质聚集体。蛋白质的错误折叠及其随后的积累成现在所谓的？淀粉样蛋白？对细胞的健康有很大的不利影响。因此，淀粉样蛋白与许多人类疾病的病因有关，如2型糖尿病、阿尔茨海默病？s和帕金森？S.尽管淀粉样蛋白沉积物具有破坏性作用，但细菌已经设计出一种仔细控制其形成的方法，从而防止它们破坏细胞。细菌也利用这些纤维结构，称为？卷发？例如促进生物膜和保护自身免受极端环境变化的影响。卷曲组装和分泌系统包括将淀粉样蛋白亚基转运到细胞外的膜孔和许多辅助/伴侣分子，其有助于调节该过程。我们建议研究的curli组装和分泌系统的结构和相互作用，以期了解其原子细节的行动模式。目前对人类淀粉样蛋白疾病的治疗是有限的，真正有效的补救措施尚未开发，因此它们代表了一个主要的公共卫生问题。我们的研究将为合理设计预防或治疗人类淀粉样蛋白疾病的新治疗方法提供指导。