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| Item Type: | Article |
|---|---|
| Title: | Aggregation of full length immunoglobulin light chains from AL amyloidosis patients is remodeled by epigallocatechin-3-gallate |
| Creators Name: | Andrich, K. and Hegenbart, U. and Kimmich, C. and Kedia, N. and Bergen, H.R. and Schönland, S. and Wanker, E.E. and Bieschke, J. |
| Abstract: | Intervention into amyloid deposition with anti-amyloid agents like the polyphenol Epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and Multiple Myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL they form amyloid deposits in vivo. We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms. We isolated nine LC from urine of AL and MM patients. We quantified their thermodynamic stabilities, and monitored their aggregation under physiological conditions by ThT fluorescence, light scattering, SDS-stability and atomic force microscopy. LC from all patients formed amyloid-like aggregates, albeit with individually different kinetics. LC existed as dimers, ~50% of which were linked by disulfide bridges. Our results suggest that cleavage into LC monomers is required for efficient amyloid formation. The kinetics of AL LC displayed a transition point in concentration dependence, which MM LC lacked. The lack of concentration dependence of MM LC aggregation kinetics suggests that conformational change of the light chain is rate-limiting for these proteins. Aggregation kinetics displayed two distinct phases, which corresponded to the formation of oligomers and amyloid fibrils, respectively. EGCG specifically inhibited the second aggregation phase and induced the formation of SDS-stable, non-amyloid LC aggregates. Our data suggest that EGCG intervention does not depend on the individual LC sequence and is similar to the mechanism observed for amyloid-{beta} and {alpha}-synuclein. |
| Keywords: | Amyloid, Immunoglobulin Fold, Multiple Myeloma, Protein Aggregation, Protein Purification, AL Amyloidosis, EGCG |
| Source: | Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Volume: | 292 |
| Number: | 6 |
| Page Range: | 2328-2344 |
| Date: | 10 February 2017 |
| Official Publication: | https://doi.org/10.1074/jbc.M116.750323 |
| PubMed: | View item in PubMed |
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