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，蛋白质分子已经演变为获得功能和可溶性状态。然而，在某些情况下，某些蛋白质分子作为单体无法保持稳定，因此将其缔合成具有纤维纤维性质的蛋白质聚集体。这些指定为淀粉样蛋白的聚集体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，是重要的生物学靶标，因为它们本质上是毒性的。了解低聚物毒性的基础对于发展下一代生物材料以及了解与淀粉样蛋白形成相关的某些异常疾病的性质至关重要，包括阿尔茨海默氏症，帕金森氏症和II型糖尿病。定义蛋白质低聚物生物学特性的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在我们对蛋白质低聚物生物学的理解中向前迈出重要一步。目前，这种互动的许多方面都是未知的。是什么使预纤维寡聚有毒？为什么只有某些蛋白质低聚物才能穿透膜？膜特性如何决定与蛋白质低聚物的相互作用？目前的项目将提供一个新颖而创新的实验和理论平台，以详细研究预先纤维蛋白质低聚物的结构性质。该项目将在与磷脂膜的选择性相互作用中散发出灯光，从而区分有毒和无毒的低聚物。为此，该研究将将核磁共振的尖端实验与晚期分子计算相结合。因此，除了应对低聚物毒性的分子起源的特定生物学靶标外，这项研究还将扩展我们研究复杂分子机制的能力，从结构生物学到合成和系统生物学以及材料科学范围。

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