Structural basis of amyloid fibril recognition by a conformation-sensitive antibody domain

构象敏感抗体结构域识别淀粉样原纤维的结构基础

• 批准号: 128368446
• 负责人: Dr. Isabel Morgado
• 金额: --
• 依托单位: Institut für Biochemie und Biotechnologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/128368446?language=en
• 关键词: Structural; basis; amyloid; fibril; recognition

Many different protein sequences can misfold into disease-associated amyloid fibrils that share a common but not fully understood structure. A promising tool in amyloid research is the generation of antibodies that recognize amyloid fibrils by their specific conformation. The Fandrich lab has previously obtained a recombinant antibody domain, termed B10, which binds in a conformation-dependent manner to different amyloid fibrils, such as fibrils derived from Alzheimer’s Aβ peptide or serum amyloid A protein. Furthermore, B10 prevents mature fibril formation by stabilizing Aβ protofibrils, the structural precursors of mature amyloid fibrils. I here propose to assess the molecular basis by which B10 is able to bind to a common epitope of different amyloid fibrils. The work will involve in-detail assessment of the B10 specificity with differently structured Aβ aggregates and amyloid fibrils from different polypeptide sequences, site-directed mutagenesis of complementarity determining regions of B10, X-ray crystallography and other biochemical methods. These studies aim to provide information about the binding of conformation-sensitive antibodies and the molecular structure of amyloid fibrils. Such data is relevant for further applications of conformation-sensitive antibodies in basic research, medical diagnosis or therapy.

许多不同的蛋白质序列可能会错误折叠成与疾病相关的淀粉样纤维，这些纤维共享一个共同的但尚未完全理解的结构。淀粉样蛋白研究中一个很有前途的工具是产生抗体，通过淀粉样蛋白纤维的特定构象识别淀粉样蛋白纤维。范德里希实验室此前已经获得了一个被称为B10的重组抗体结构域，它以构象依赖的方式与不同的淀粉样纤维结合，例如来自阿尔茨海默氏症Aβ肽或血清淀粉样蛋白A的纤维。此外，B10通过稳定Aβ原纤维(成熟淀粉样纤维的结构前体)来防止成熟纤维的形成。我在这里建议评估B10能够与不同淀粉样蛋白纤维的共同表位结合的分子基础。这项工作将包括用不同多肽序列中不同结构的Aβ聚集体和淀粉样纤维详细评估B10的特异性，B10互补决定区的定点突变，X射线结晶学和其他生化方法。这些研究旨在提供有关构象敏感抗体的结合和淀粉样蛋白纤维的分子结构的信息。这些数据对构象敏感抗体在基础研究、医学诊断或治疗中的进一步应用具有重要意义。