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The mechanism for amyloid formation in a model peptide

模型肽中淀粉样蛋白形成的机制

基本信息

批准号：
BB/D000718/1
负责人：
David John Wales
金额：
$ 28.46万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FD000718%2F1
关键词：
mechanism amyloid formation model peptide

项目摘要

Proteins are chains constructed from twenty different amino acids, which must fold up into a biologically active form after they are synthesised in cells. The functional proteins play essential structural and catalytic roles in all living organisms. However, when proteins misfold they can form well-defined aggregates, generically known as amyloid, and it is now known that a wide variety of proteins can be induced to form amyloid under appropriate conditions. Amyloid formation has been implicated in a number of serious diseases, such as Alzheimer's (senile dementia), bovine spongiform encephalopathy (mad cow disease), and Creutzfeld-Jacob disease (the human form of mad cow disease). It is also associated with diabetic conditions caused by poorly chosen diets, as well as inherited traits, such as early onset forms of dementia. The realisation that aggregation can occur for a wide range of proteins under suitable conditions is relatively recent, and many fundamental questions concerning amyloid formation are still unresolved. Although there is general agreement that aggregation is induced by a conformational change from the native structure to a generic sheet-like structure (related to that in silk), little is known about the mechanistic details of this process, and discovering how it occurs is a key priority for the development of treatment for amyloid diseases. The conformational change appears to be self-propagating, since the rate increases as the reaction progresses. The goal of this project is to elucidate the mechanism by which the structure changes from a compact state into amyloid for a recently designed artificial protein. We aim to resolve this mechanism at an atomic level of detail using newly developed theory and computer simulation techniques. The results will provide important new insights into amyloid formation. In particular, more specific and precise methods to prevent and perhaps reverse amyloid formation may emerge, with important implications for the treatment of human disease, including aspects of ageing and conditions related to obesity and poorly chosen diets.

蛋白质是由二十种不同的氨基酸组成的链，它们在细胞中合成后必须折叠成具有生物活性的形式。这些功能蛋白在所有生物体中都发挥着重要的结构和催化作用。然而，当蛋白质错误折叠时，它们可以形成定义明确的聚集体，通常被称为淀粉样蛋白，现在已经知道，在适当的条件下，可以诱导多种蛋白质形成淀粉样蛋白。淀粉样蛋白的形成与许多严重疾病有关，如阿尔茨海默氏症(老年性痴呆)、牛海绵状脑病(疯牛病)和克雅氏病(人类形式的疯牛病)。它还与选择不当的饮食引起的糖尿病疾病以及遗传特征有关，例如早发性痴呆症。人们意识到，在合适的条件下，多种蛋白质可以发生聚集，这一认识是相对较新的，关于淀粉样蛋白形成的许多基本问题仍然没有解决。虽然人们普遍认为聚集是由天然结构到普通片状结构(与蚕丝中的结构有关)的构象变化引起的，但对这一过程的机制细节知之甚少，发现它是如何发生的是发展淀粉样蛋白疾病治疗的关键优先事项。构象变化似乎是自蔓延的，因为随着反应的进行，变化的速度会增加。这个项目的目标是阐明最近设计的一种人造蛋白质的结构从致密状态转变为淀粉样蛋白的机制。我们的目标是利用最新发展的理论和计算机模拟技术，在原子水平上详细解决这一机制。这一结果将为淀粉样蛋白的形成提供重要的新见解。特别是，可能会出现更具体和更精确的方法来防止甚至逆转淀粉样蛋白的形成，这对人类疾病的治疗具有重要意义，包括衰老和与肥胖有关的条件以及选择不当的饮食。