Understanding the Critical Step for the Cellular Toxicity of Protein Oligomers.

了解蛋白质寡聚物细胞毒性的关键步骤。

• 批准号: BB/M023923/1
• 负责人: Alfonso De Simone
• 金额: $ 46.41万
• 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: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM023923%2F1
• 关键词: Understanding; Critical; Step; Cellular; Toxicity

Protein molecules have evolved to attain functional and soluble states under normal and physiological conditions. In some cases, however, some protein molecules are unable to remain stable as monomers and consequently associate into protein aggregates having a fibrilar nature. These aggregates, designated as amyloids, have a large biological relevance and are in fact considered attractive structures for targeting new generations of biomaterials. Early states of amyloids, namely protein oligomers, are important biological targets as they can be inherently toxic. Understanding the bases of the oligomers toxicity is essential to develop the next generation of biomaterials as well as to understand the nature of some aberrant diseases that are connected to the amyloid formation, including Alzheimer's, Parkinson's and type II diabetes. An crucial step that defines the biological properties of protein oligomers is the interaction with the cell membrane. This interaction represents the key event in the toxicity of protein oligomers. Understanding the molecular basis of the interaction with the membrane will provide a significant step forward in our understanding of the biology of protein oligomers. Many aspects of this interaction are currently unknown. What makes a prefibrilar oligomer toxic? Why only some protein oligomers are able to penetrate the membrane? How the membrane properties dictate the interplay with protein oligomers?The present project will provide a novel and innovative platform of experiments and theory to investigate in detail on the structural nature of prefibrilar protein oligomers. The project will shed light in the selective interaction with phospholipid membranes that distinguishes between toxic and non-toxic oligomers. To this aim, the research will combine cutting-edge experiments of nuclear magnetic resonance with advanced molecular computation. Thus, in addition to the specific biological target of tackling the molecular origins of the oligomers toxicity, this research will extend our ability to study complex molecular mechanisms, with a large number of applications ranging from structural biology to synthetic and system biology and to material sciences.

在正常和生理条件下，蛋白质分子已经进化到功能和可溶性状态。然而，在某些情况下，一些蛋白质分子不能作为单体保持稳定，因此结合成具有原纤维性质的蛋白质聚集体。这些聚集体，被称为淀粉样蛋白，具有很大的生物学相关性，实际上被认为是针对新一代生物材料的有吸引力的结构。淀粉样蛋白的早期状态，即蛋白质低聚物，是重要的生物学靶点，因为它们可能具有固有的毒性。了解低聚物毒性的基础对开发下一代生物材料以及了解与淀粉样蛋白形成有关的一些异常疾病的本质至关重要，包括阿尔茨海默氏症、帕金森病和II型糖尿病。确定蛋白质低聚物生物学特性的一个关键步骤是与细胞膜的相互作用。这种相互作用代表了蛋白质低聚物毒性的关键事件。了解与膜相互作用的分子基础将为我们理解蛋白质低聚物的生物学提供重要的一步。这种相互作用的许多方面目前尚不清楚。是什么使纤维前低聚物有毒？为什么只有一些蛋白质低聚物能够穿透膜？膜的性质如何决定与蛋白质低聚物的相互作用？本项目将为深入研究原纤维前蛋白低聚物的结构性质提供一个新颖、创新的实验和理论平台。该项目将阐明与磷脂膜的选择性相互作用，区分有毒和无毒低聚物。为此，研究将把核磁共振的尖端实验与先进的分子计算结合起来。因此，除了解决低聚物毒性的分子起源的特定生物学目标外，本研究将扩展我们研究复杂分子机制的能力，具有从结构生物学到合成生物学和系统生物学以及材料科学的大量应用。

项目成果

Backbone NMR assignments of HypF-N under conditions generating toxic and non-toxic oligomers.

• DOI: 10.1007/s12104-018-9822-7
• 发表时间: 2018-10
• 期刊: Biomolecular NMR assignments
• 影响因子: 0.9
• 作者: Patel JR;Xu Y;Capitini C;Chiti F;De Simone A
• 通讯作者: De Simone A