Structural Basis of Serpin Polymerisation

我们这个时代的许多最突出的疾病都是由蛋白质的自我结合引起的。这些疾病包括阿尔茨海默氏症、S病、亨廷顿病、S病、帕金森病、S病以及疯牛病、瘙痒病和克雅氏病等蛋白脑病。这些疾病被归类为构象疾病，因为潜在的蛋白质改变了它的构象，在细胞内外沉积了稳定的聚集体。一种名为蛇类的蛋白质家族也可以自结合，通过一种称为聚合的机制创造稳定的细胞间沉积，导致痴呆症、肝硬变和血栓等疾病。人们普遍认为，任何一种构象疾病的成功治疗设计都需要详细了解导致自我关联的构象变化。在这项授权中，我们研究了蛇是如何通过结合使用生化和结构技术进行聚合的。我们最近解决了一种稳定的丝氨酸二聚体的结构，揭示了一种意想不到的大规模连接，并解释了聚合物的感染性，并提出了单体如何成为聚合体。我们将确定这一机制是否是蛇类在一般情况下和活细胞内聚合的基础。其结果将是单体和聚合物物种的分子图像，从而允许合理设计药物来减缓、防止甚至逆转致病蛋白的结合。

Many of the most prominent diseases of our age are cause by the self-association of proteins. These include Alzheimer?s, Huntington?s, Parkinson?s Diseases and the prion encephalopathies, such as Mad-Cow Disease, Scrapie and Creutzfeldt-Jakob Disease. These disorders have been classified as conformational diseases because the underlying protein alters its conformation to deposit stable aggregates either within or outside of cells. A family of proteins called the serpins can also self-associate to create stable intercellular deposits, through a mechanism called polymerisation, leading to dementia, cirrhosis and thrombosis, among other diseases. It is generally accepted that the design of successful treatment for any of the conformational diseases will require a detailed understanding of the conformational changes that lead to self-association. In this grant we investigate how serpins polymerise by using a combination of biochemical and structural techniques. We have recently solved a structure of a stable serpin dimer that revealed an unexpected, large-scale linkage and explained the infectivity of polymers and suggested how monomers become polymerogenic. We will determine if this mechanism underlies polymerisation of serpins in general and inside of living cells. The result will be a molecular picture of the monomeric and polymeric species to allow the rational design of drugs to slow, prevent or even reverse pathogenic protein association.