title: Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains.
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.
authors.affiliation: Center for Integrated Protein Science at Department Chemie, Technische Universität München Lichtenbergstrasse 4, 85747 Garching, Germany.|Helmholtz-Zentrum München (HMGU), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hora
authors.affiliation: Institute of Complex Systems: Structural Biochemistry at Forschungszentrum Jülich, 52425 Jülich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Carballo-Pacheco
authors.affiliation: Center for Integrated Protein Science at Department Chemie, Technische Universität München Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Weber
authors.affiliation: Center for Integrated Protein Science at Department Chemie, Technische Universität München Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Vanessa K
authors.initials: VK
authors.lastname: Morris
authors.affiliation: Center for Integrated Protein Science at Department Chemie, Technische Universität München Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Wittkopf
authors.affiliation: Center for Integrated Protein Science at Department Chemie, Technische Universität München Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Buchner
authors.affiliation: Institute of Complex Systems: Structural Biochemistry at Forschungszentrum Jülich, 52425 Jülich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strodel
authors.affiliation: Center for Integrated Protein Science at Department Chemie, Technische Universität München Lichtenbergstrasse 4, 85747 Garching, Germany.|Helmholtz-Zentrum München (HMGU), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Reif
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011232:Chemical Precipitation; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation / Q000235:genetics; D011392:Proline / Q000378:metabolism; D066329:Protein Aggregates; D016415:Sequence Alignment
chemical_list: D000682:Amyloid; D007147:Immunoglobulin Light Chains; D066329:Protein Aggregates; D002392:Catechin; D011392:Proline; C045651:epigallocatechin gallate