Inhibition of amyloid fibril formation in the variable domain of λ6 light chain mutant Wil caused by the interaction between its unfolded state and epigallocatechin-3-O-gallate

Yoshito Abe, Naoki Odawara, Nantanat Aeimhirunkailas, Hinako Shibata, Naoki Fujisaki, Hirofumi Tachibana, Tadashi Ueda

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Light chains are abnormally overexpressed from disordered monoclonal B-cells and form amyloid fibrils, which are then deposited on the affected organ, leading to a form of systemic amyloidosis known as AL (Amyloid Light chain) amyloidosis. A green tea catechin, epigallocatechin-3-O-gallate (EGCG), which is thought to inhibit various amyloidoses, is a potent inhibitor of amyloid fibril formation in AL amyloidosis.

METHODS: An amyloidogenic variable domain in λ6 light chain mutant, Wil was incubated in the presence of EGCG. The incubation products were analyzed by SDS-PAGE and reverse-phase HPLC. The interaction between Wil and EGCG was observed by using NMR and tryptophan fluorescence.

RESULTS: EGCG inhibited the amyloid fibril formation of Wil at pH 7.5 and 42 °C. Under these conditions, most Wil populations were in the unfolded state and several chemical reactions, i.e., oxidation and/or covalent bond oligomerization could be induced by auto-oxidated EGCG. Moreover, we found that EGCG bound to the unfolded state of Wil with higher affinity (Kd = 7 μM).

CONCLUSIONS: Inhibition of amyloid fibril formation of Wil was caused by 1) EGCG binding to unfolded state rather than folded state and 2) chemical modifications of Wil by auto oxidation of EGCG.

GENERAL SIGNIFICANCE: In the competitive formation of amyloid fibrils and off-pathway oligomers, EGCG produces the latter immediately after it preferentially binds to the unfolded state. It may be general mechanism of EGCG inhibition for amyloidosis.

Original languageEnglish
Pages (from-to)2570-2578
Number of pages9
JournalBiochimica et Biophysica Acta - General Subjects
Volume1862
Issue number12
DOIs
Publication statusPublished - Dec 2018

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Amyloid
Light
Amyloidosis
epigallocatechin gallate
Oxidation
Oligomerization
Covalent bonds
Catechin
Chemical modification
Tea
Oligomers
Tryptophan
Polyacrylamide Gel Electrophoresis
Chemical reactions
B-Lymphocytes
Fluorescence
High Pressure Liquid Chromatography
Cells
Nuclear magnetic resonance

Cite this

@article{73ea18c307644f9c87319da6b2e73e94,
title = "Inhibition of amyloid fibril formation in the variable domain of λ6 light chain mutant Wil caused by the interaction between its unfolded state and epigallocatechin-3-O-gallate",
abstract = "BACKGROUND: Light chains are abnormally overexpressed from disordered monoclonal B-cells and form amyloid fibrils, which are then deposited on the affected organ, leading to a form of systemic amyloidosis known as AL (Amyloid Light chain) amyloidosis. A green tea catechin, epigallocatechin-3-O-gallate (EGCG), which is thought to inhibit various amyloidoses, is a potent inhibitor of amyloid fibril formation in AL amyloidosis.METHODS: An amyloidogenic variable domain in λ6 light chain mutant, Wil was incubated in the presence of EGCG. The incubation products were analyzed by SDS-PAGE and reverse-phase HPLC. The interaction between Wil and EGCG was observed by using NMR and tryptophan fluorescence.RESULTS: EGCG inhibited the amyloid fibril formation of Wil at pH 7.5 and 42 °C. Under these conditions, most Wil populations were in the unfolded state and several chemical reactions, i.e., oxidation and/or covalent bond oligomerization could be induced by auto-oxidated EGCG. Moreover, we found that EGCG bound to the unfolded state of Wil with higher affinity (Kd = 7 μM).CONCLUSIONS: Inhibition of amyloid fibril formation of Wil was caused by 1) EGCG binding to unfolded state rather than folded state and 2) chemical modifications of Wil by auto oxidation of EGCG.GENERAL SIGNIFICANCE: In the competitive formation of amyloid fibrils and off-pathway oligomers, EGCG produces the latter immediately after it preferentially binds to the unfolded state. It may be general mechanism of EGCG inhibition for amyloidosis.",
author = "Yoshito Abe and Naoki Odawara and Nantanat Aeimhirunkailas and Hinako Shibata and Naoki Fujisaki and Hirofumi Tachibana and Tadashi Ueda",
note = "Copyright {\circledC} 2018 Elsevier B.V. All rights reserved.",
year = "2018",
month = "12",
doi = "10.1016/j.bbagen.2018.08.006",
language = "English",
volume = "1862",
pages = "2570--2578",
journal = "Biochimica et Biophysica Acta - General Subjects",
issn = "0304-4165",
publisher = "Elsevier",
number = "12",

}

TY - JOUR

T1 - Inhibition of amyloid fibril formation in the variable domain of λ6 light chain mutant Wil caused by the interaction between its unfolded state and epigallocatechin-3-O-gallate

AU - Abe, Yoshito

AU - Odawara, Naoki

AU - Aeimhirunkailas, Nantanat

AU - Shibata, Hinako

AU - Fujisaki, Naoki

AU - Tachibana, Hirofumi

AU - Ueda, Tadashi

N1 - Copyright © 2018 Elsevier B.V. All rights reserved.

PY - 2018/12

Y1 - 2018/12

N2 - BACKGROUND: Light chains are abnormally overexpressed from disordered monoclonal B-cells and form amyloid fibrils, which are then deposited on the affected organ, leading to a form of systemic amyloidosis known as AL (Amyloid Light chain) amyloidosis. A green tea catechin, epigallocatechin-3-O-gallate (EGCG), which is thought to inhibit various amyloidoses, is a potent inhibitor of amyloid fibril formation in AL amyloidosis.METHODS: An amyloidogenic variable domain in λ6 light chain mutant, Wil was incubated in the presence of EGCG. The incubation products were analyzed by SDS-PAGE and reverse-phase HPLC. The interaction between Wil and EGCG was observed by using NMR and tryptophan fluorescence.RESULTS: EGCG inhibited the amyloid fibril formation of Wil at pH 7.5 and 42 °C. Under these conditions, most Wil populations were in the unfolded state and several chemical reactions, i.e., oxidation and/or covalent bond oligomerization could be induced by auto-oxidated EGCG. Moreover, we found that EGCG bound to the unfolded state of Wil with higher affinity (Kd = 7 μM).CONCLUSIONS: Inhibition of amyloid fibril formation of Wil was caused by 1) EGCG binding to unfolded state rather than folded state and 2) chemical modifications of Wil by auto oxidation of EGCG.GENERAL SIGNIFICANCE: In the competitive formation of amyloid fibrils and off-pathway oligomers, EGCG produces the latter immediately after it preferentially binds to the unfolded state. It may be general mechanism of EGCG inhibition for amyloidosis.

AB - BACKGROUND: Light chains are abnormally overexpressed from disordered monoclonal B-cells and form amyloid fibrils, which are then deposited on the affected organ, leading to a form of systemic amyloidosis known as AL (Amyloid Light chain) amyloidosis. A green tea catechin, epigallocatechin-3-O-gallate (EGCG), which is thought to inhibit various amyloidoses, is a potent inhibitor of amyloid fibril formation in AL amyloidosis.METHODS: An amyloidogenic variable domain in λ6 light chain mutant, Wil was incubated in the presence of EGCG. The incubation products were analyzed by SDS-PAGE and reverse-phase HPLC. The interaction between Wil and EGCG was observed by using NMR and tryptophan fluorescence.RESULTS: EGCG inhibited the amyloid fibril formation of Wil at pH 7.5 and 42 °C. Under these conditions, most Wil populations were in the unfolded state and several chemical reactions, i.e., oxidation and/or covalent bond oligomerization could be induced by auto-oxidated EGCG. Moreover, we found that EGCG bound to the unfolded state of Wil with higher affinity (Kd = 7 μM).CONCLUSIONS: Inhibition of amyloid fibril formation of Wil was caused by 1) EGCG binding to unfolded state rather than folded state and 2) chemical modifications of Wil by auto oxidation of EGCG.GENERAL SIGNIFICANCE: In the competitive formation of amyloid fibrils and off-pathway oligomers, EGCG produces the latter immediately after it preferentially binds to the unfolded state. It may be general mechanism of EGCG inhibition for amyloidosis.

U2 - 10.1016/j.bbagen.2018.08.006

DO - 10.1016/j.bbagen.2018.08.006

M3 - Article

C2 - 30251653

VL - 1862

SP - 2570

EP - 2578

JO - Biochimica et Biophysica Acta - General Subjects

JF - Biochimica et Biophysica Acta - General Subjects

SN - 0304-4165

IS - 12

ER -