Molecular insights into the misfolding pathways of antibody light chain proteins

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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.