Molecular insights into the misfolding pathways of antibody light chain proteins

对抗体轻链蛋白错误折叠途径的分子见解

• 批准号: 517295284
• 负责人: Professor Dr. Bernd Reif
• 金额: --
• 依托单位: Professur für Festkörper-NMR-Spektroskopie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/517295284?language=en
• 关键词: Molecular; insights; into; misfolding; pathways

It is the aim of the project to obtain molecular insights into the mechanism of antibody light chain (LC) misfolding involved in AL amyloidosis. We would like to work out mechanistic differences in the aggregation of lambda and kappa LCs. In this context, we will focus on the VL variable domain as well as on the full-length light chain protein. We will study germline as well as patient protein and investigate point mutants that are known to induce amyloidogenicity. We will characterize dimerization, local unfolding of the light chain, and formation of oligomeric intermediates. Finally, we will investigate amyloid fibril structures and their dynamics to derive general principles for AL amyloid fibril formation. To carry out these experiments, we employ a broad range of biophysical techniques with a focus on solution-state and MAS solid-state NMR spectroscopy.

该项目的目的是获得抗体轻链（LC）错误折叠参与AL淀粉样变性的分子机制。我们想找出λ和kappa LCs聚集的机制差异。在这种情况下，我们将重点关注VL可变结构域以及全长轻链蛋白。我们将研究种系蛋白和患者蛋白，并研究已知可诱导淀粉样变性的点突变体。我们将描述二聚化，轻链的局部展开，以及低聚中间体的形成。最后，我们将研究淀粉样蛋白纤维结构及其动力学，以得出AL淀粉样蛋白纤维形成的一般原理。为了进行这些实验，我们采用了广泛的生物物理技术，重点是溶液态和MAS固态核磁共振光谱。