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Structural insight into IAPP-derived amyloid inhibitors and their mechanism of action.
Adv. Mater. 59, 5820-5830 (2020)
Publ. Version/Full Text
Research data
DOI
Designed peptides derived from the islet amyloid polypeptide (IAPP) cross-amyloid interaction surface with Aβ (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of Aβ amyloid self-assembly. However, the molecular mechanism of their function is not well understood. Using solution-state and solid-state NMR spectroscopy in combination with ensemble-averaged dynamics simulations and other biophysical methods including TEM, fluorescence spectroscopy and microscopy, and DLS, we characterize ISM structural preferences and interactions. We find that the ISM peptide R3-GI is highly dynamic, can adopt a β-like structure, and oligomerizes into colloid-like assemblies in a process that is reminiscent of liquid–liquid phase separation (LLPS). Our results suggest that such assemblies yield multivalent surfaces for interactions with Aβ40. Sequestration of substrates into these colloid-like structures provides a mechanistic basis for ISM function and the design of novel potent anti-amyloid molecules.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Amyloid-bildung ; Amyloid-inhibitoren ; Aβ ; Festkörper-nmr-spektroskopie ; Peptide
ISSN (print) / ISBN
0935-9648
e-ISSN
1521-4095
Journal
Advanced materials
Quellenangaben
Volume: 59,
Issue: 14,
Pages: 5820-5830
Publisher
Wiley
Publishing Place
Weinheim
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)