Abstract
Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs). The huge variety of antibody sequences puts a serious challenge to drug discovery. The green tea polyphenol epigallocatechin-3-gallate (EGCG) is known to interfere with fibril formation in general. Here we present solution- and solid-state NMR studies as well as MD simulations to characterise the interaction of EGCG with LC variable domains. We identified two distinct EGCG binding sites, both of which include a proline as an important recognition element. The binding sites were confirmed by site-directed mutagenesis and solid-state NMR analysis. The EGCG-induced protein complexes are unstructured. We propose a general mechanistic model for EGCG binding to a conserved site in LCs. We find that EGCG reacts selectively with amyloidogenic mutants. This makes this compound a promising lead structure, that can handle the immense sequence variability of antibody LCs.
Highlights
Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs)
Systemic antibody light chain amyloidosis (AL amyloidosis) is a systemic disease caused by amyloid fibril formation of free immunoglobulin light chains (LCs) in the serum[1]
We used the S20N mutant for initial experiments to study the interaction with EGCG (Fig. 1a), because its fibril formation can be controlled by experimental settings
Summary
Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs). We find that EGCG reacts selectively with amyloidogenic mutants This makes this compound a promising lead structure, that can handle the immense sequence variability of antibody LCs. Systemic antibody light chain amyloidosis (AL amyloidosis) is a systemic disease caused by amyloid fibril formation of free immunoglobulin light chains (LCs) in the serum[1]. Unstable sequences have higher propensity to aggregate, but too low stability can prevent fibrillogenesis[17], indicating that partially unfolded states are involved in the pathway to fibril formation. These intermediates might be populated in vitro at acidic or otherwise destabilising conditions[18,19,20,21]. Methylene blue and sulfasalazine have been suggested to prevent fibril formation of immunoglobulin LCs by stabilising the more stable LC dimer[29]
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