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Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains.
Sci. Rep. 7:41515 (2017)
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.
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4.259
1.401
16
21
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Primary Systemic Amyloidosis; V-l Domain; Green Tea; Al Amyloidosis; Thermal-stability; Crystal-structure; Variable Domains; Nmr-spectroscopy; Fibril Formation; Constant-region
Language
english
Publication Year
2017
HGF-reported in Year
2017
ISSN (print) / ISBN
2045-2322
e-ISSN
2045-2322
Journal
Scientific Reports
Quellenangaben
Volume: 7,
Article Number: 41515
Publisher
Nature Publishing Group
Publishing Place
London
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Enabling and Novel Technologies
PSP Element(s)
G-503090-001
PubMed ID
28128355
WOS ID
WOS:000392794800001
Scopus ID
85010966182
Erfassungsdatum
2017-03-21