Title
Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains
Author
Manuel Hora, Martin Carballo-Pacheco, Benedikt Weber, Vanessa K. Morris, Antje Wittkopf, Johannes Buchner, Birgit Strodel, Bernd Reif
Year
2017
Journal
Scientific Reports
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.
Full Article
Instrument
J-715
Keywords
Circular dichroism, Secondary structure, Thermal stability, Thermodynamics, Biochemistry