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Structural Insight into IAPP-Derived Amyloid Inhibitors and Their Mechanism of Action.
- Source :
-
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2020 Mar 27; Vol. 59 (14), pp. 5771-5781. Date of Electronic Publication: 2020 Jan 28. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
- Subjects :
- Amino Acid Sequence
Amyloid beta-Peptides metabolism
Microscopy, Fluorescence
Molecular Dynamics Simulation
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments metabolism
Peptides metabolism
Substrate Specificity
Amyloid beta-Peptides antagonists & inhibitors
Islet Amyloid Polypeptide chemistry
Peptide Fragments antagonists & inhibitors
Peptides chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1521-3773
- Volume :
- 59
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Angewandte Chemie (International ed. in English)
- Publication Type :
- Academic Journal
- Accession number :
- 31863711
- Full Text :
- https://doi.org/10.1002/anie.201914559