Designed peptides derived from the islet amyloid polypeptide (IAPP) cross-amyloid interaction surface with A beta (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of A beta 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 beta-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 A beta 40. Sequestration of substrates into these colloid-like structures provides a mechanistic basis for ISM function and the design of novel potent anti-amyloid molecules.
Structural insight into IAPP-derived amyloid inhibitors and their mechanism of action / Z. Niu, E. Prade, E. Malideli, K. Hille, A. Jussupow, Y. Mideksa, L. Yan, C. Qian, M. Fleisch, A.C. Messias, R. Sarkar, M. Sattler, D.C. Lamb, M.J. Feige, C. Camilloni, A. Kapurniotu, B. Reif. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - 59(2020), pp. 5771-5781. [10.1002/anie.201914559]
Structural insight into IAPP-derived amyloid inhibitors and their mechanism of action
C. Camilloni;
2020
Abstract
Designed peptides derived from the islet amyloid polypeptide (IAPP) cross-amyloid interaction surface with A beta (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of A beta 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 beta-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 A beta 40. Sequestration of substrates into these colloid-like structures provides a mechanistic basis for ISM function and the design of novel potent anti-amyloid molecules.File | Dimensione | Formato | |
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