Molecular insights into the misfolding pathways of antibody light chain proteins

该项目的目的是从分子水平深入了解AL淀粉样变性中抗体轻链（LC）错误折叠的机制。我们想找出Lambda和Kappa LC聚集的机理差异。在这种情况下，我们将集中在VL可变结构域以及全长轻链蛋白。我们将研究生殖系以及患者蛋白质和调查点突变，已知诱导淀粉样蛋白。我们将描述轻链的二聚化、局部解折叠和寡聚中间体的形成。最后，我们将研究淀粉样纤维的结构和动力学，以得出AL淀粉样纤维形成的一般原则。为了进行这些实验，我们采用了广泛的生物物理技术，重点是溶液状态和MAS固态NMR光谱。

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.