Cryo-EM structures of AL amyloid fibrils from human heart

人心脏 AL 淀粉样原纤维的冷冻电镜结构

• 批准号: 422469128
• 负责人: Professor Dr. Marcus Fändrich
• 金额: --
• 依托单位: Institut für Proteinbiochemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422469128?language=en
• 关键词: Cryo; EM; structures; AL; amyloid

AL amyloid fibrils are key pathogenic agents in systemic AL amyloidosis. They are morphologically variable between different patients but little is known about their exact structures. For example, it is so far remained unclear whether different cases of cardiac amyloidosis involve similarly folded conformations or misfolded states of the fibril protein. Using AL amyloid fibril extracted from the explanted hearts of patients with a strong cardiac involvement we will address the following aims: (i) To extract Lambda-AL amyloid fibrils from cardiac amyloid deposits. (ii) To determine the cryo electron microscopy structure of a patient-derived AL amyloid fibril. (iii) To determine the structural diversity of Lambda-AL amyloid fibrils. (iv) To compare AL amyloid fibrils with light chain-derived amyloid-like fibrils. Through this work we will test the hypothesis that fibril formation in cardiac AL amyloidosis involves common structural themes for the assembly in vivo. Our work intends primarily to promote a better understanding of the molecular agents underlying systemic AL amyloidosis, the structural specifics of AL amyloid fibrils and their variability. Moreover, it will help us to further clarify the mechanism of fibril formation as it occur under natural conditions inside a patient.

Al淀粉样蛋白原纤维是全身性淀粉样变性的关键致病剂。它们在不同患者之间是形态上变化的，但对它们的确切结构知之甚少。例如，到目前为止，尚不清楚不同的心脏淀粉样变性病例是否涉及类似折叠的构象或原纤维蛋白的错误折叠状态。使用从具有较强心脏参与的患者的植内性心脏中提取的Al淀粉样蛋白原纤维，我们将解决以下目的：（i）从心脏淀粉样蛋白沉积物中提取Lambda-Al淀粉样蛋白原纤维。 （ii）确定患者衍生的Al淀粉样纤维的冷冻电子显微镜结构。 （iii）确定lambda-al淀粉样纤维的结构多样性。 （iv）将Al淀粉样蛋白原纤维与轻链衍生的淀粉样蛋白样原纤维进行比较。通过这项工作，我们将检验以下假设：心脏淀粉样变性中的原纤维形成涉及体内组装的常见结构主题。我们的工作主要旨在更好地促进对全身性AL淀粉样变性的分子剂，Al淀粉样蛋白原纤维的结构细节及其变异性的更好理解。此外，这将有助于我们进一步阐明纤维形成的机理，因为它在患者内部的自然条件下发生。