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How epigallocatechin gallate binds and assembles oligomeric forms of human alpha-synuclein
Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review
DOI
- https://doi.org/10.1016/j.jbc.2021.100788
Forlagets udgivne version
- Camilla B Andersen ,
- Yuichi Yoshimura ,
- Janni Nielsen
- Daniel E Otzen
- Frans A A Mulder
The intrinsically disordered human protein α-synuclein (αSN) can self-associate into oligomers and amyloid fibrils. Several lines of evidence suggest that oligomeric αSN is cytotoxic, making it important to devise strategies to either prevent oligomer formation and/or inhibit the ensuing toxicity. (-)-epigallocatechin gallate (EGCG) has emerged as a molecular modulator of αSN self-assembly, as it reduces the flexibility of the C-terminal region of αSN in the oligomer and inhibits the oligomer’s ability to perturb phospholipid membranes and induce cell death. However, a detailed structural and kinetic characterization of this interaction is still lacking. Here, we use liquid-state NMR spectroscopy to investigate how EGCG interacts with monomeric and oligomeric forms of αSN. We find that EGCG can bind to all parts of monomeric αSN but exhibits highest affinity for the N-terminal region. Monomeric αSN binds 54 molecules of EGCG in total during oligomerization. Furthermore, kinetic data suggest that EGCG dimerization is coupled with the αSN association reaction. In contrast, preformed oligomers only bind ~7 EGCG molecules per protomer, in agreement with the more compact nature of the oligomer compared with the natively unfolded monomer. In previously conducted cell assays, as little as 0.36 EGCG per αSN reduce oligomer toxicity by 50%. Our study thus demonstrates that αSN cytotoxicity can be inhibited by small molecules at concentrations at least an order of magnitude below full binding capacity. We speculate this is due to cooperative binding of protein-stabilized EGCG dimers, which in turn implies synergy between protein association and EGCG dimerization.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 100788 |
| Tidsskrift | The Journal of Biological Chemistry |
| Vol/bind | 296 |
| Antal sider | 10 |
| ISSN | 0021-9258 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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