Total protein synthesis: a new tool for studies of the structure and stability of amyloid fibrils

淀粉样蛋白疾病包括许多众所周知的疾病，如阿尔茨海默病和新的变异克鲁兹菲尔德-雅各布病。所有这些条件都涉及蛋白质分子聚集成大的不容溶解的纤维。这项研究的目的是在分子水平上了解蛋白质如何组装成淀粉样纤维。我们的目标是通过改变β-2微球蛋白的结构来实现这一点，β-2微球蛋白是一种参与淀粉样蛋白的蛋白质，影响所有长期进行肾脏透析的人，并研究蛋白质序列的变化如何改变蛋白质形成淀粉样纤维的能力。在这项特殊的研究中，我们将改变蛋白质的基本骨架结构，而这种操纵不能使用生化方法进行。相反，我们将使用化学方法合成整个蛋白质结构，使每个酰胺键都在实验室反应器中。化学方法没有生物化学那样的局限性，因此我们可以对目标蛋白质的基本结构进行深刻的改变。通过研究蛋白质结构的这些变化如何改变其形成淀粉样纤维的能力，我们将阐明有关淀粉样纤维的结构和稳定性的新信息，这些信息将为未来开发针对这些致命疾病的新疗法提供信息。

Amyloid diseases include many well known conditions such as Alzheimer's disease and new variant Cruetzfeld-Jakob disease. All these conditions involve the aggregation of protein molecules into large insoluble fibrils. The purpose of this research is to understand how proteins assemble into amyloid fibrils at the molecular level. We aim to achieve this by altering the structure of beta-2-microglobulin, a protein involved in an amyloid condition that affects all people on long-term renal dialysis, and to investigate how the changes to the protein sequence alter the ability of the protein to form amyloid fibrils. In this particular study we will make changes to the fundamental backbone structure of the protein and such manipulations can not be made using biochemical methods. Instead we will synthesise the whole protein structure using chemistry making each amide bond in a laboratory reactor. The chemical approach does not have the same limitations as biochemistry and so we can make profound changes to the fundamental structure of the target protein. By studying how these changes to the protein structure alter its ability to form amyloid fibres we will elucidate new information about the structure and stability of amyloid fibrils that will inform future work to develop new therapies against these fatal diseases.