Abstract
Little structural information is available so far on amyloid fibrils consisting of immunoglobulin light chains. It is not understood which features of the primary sequence of the protein result in fibril formation. We report here MAS solid-state NMR studies to identify the structured core of κ-type variable domain light chain fibrils. The core contains residues of the CDR2 and the β-strands D, E, F and G of the native immunoglobulin fold. The assigned core region of the fibril is distinct in comparison to the core identified in a previous solid-state NMR study on AL-09 by Piehl at. al, suggesting that VL fibrils can adopt different topologies. In addition, we investigated a soluble oligomeric intermediate state, previously termed the alternatively folded state (AFS), using NMR and FTIR spectroscopy. The NMR oligomer spectra display a high degree of similarity when compared to the fibril spectra, indicating a high structural similarity of the two aggregation states. Based on comparison to the native state NMR chemical shifts, we suggest that fibril formation via domain-swapping seems unlikely. Moreover, we used our results to test the quality of different amyloid prediction algorithms.
Highlights
Antibody light chain amyloidosis (AL amyloidosis) is a rare disease caused by amyloid formation of immunoglobulin light chains (LCs) [1,2]
We report here a MAS ssNMR spectroscopic analysis of amyloid fibrils and oligomers formed by the variable domain (VL) domain of MAK33
We reported on the structured core residues of an immunoglobulin VL-κ sequence in the amyloid fibril and oligomeric state
Summary
Antibody light chain amyloidosis (AL amyloidosis) is a rare disease caused by amyloid formation of immunoglobulin light chains (LCs) [1,2]. An underlying B-cell dyscrasia causes overproduction and secretion of LCs. In the case of an aggregation-prone LC sequence, this can result in formation of oligomeric intermediates and further of fibrils, which deposit in the inner organs, causing systemic amyloidosis. Non-fibrillar oligomers have aroused interest of the research community due to their cytotoxicity as well as their role as folding intermediates [6]. Oligomers have been reported for several amyloid-forming proteins and peptides [7]. In many cases, these oligomers appear to be the most cytotoxic species [8,9].
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