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Niu, Z. ; Prade, E.* ; Malideli, E.* ; Hille, K.* ; Jussupow, A.* ; Mideksa, Y.G.* ; Yan, L.M.* ; Qian, C.* ; Fleisch, M. ; Messias, A.C. ; Sarkar, R. ; Sattler, M. ; Lamb, D.C.* ; Feige, M.J.* ; Camilloni, C.* ; Kapurniotu, A.* ; Reif, B.

Structural insight into IAPP-derived amyloid inhibitors and their mechanism of action.

Angew. Chem.-Int. Edit. 59, 2-13 (2020)
Verlagsversion Forschungsdaten DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Amyloid Formation ; Amyloid Inhibitors ; A Beta ; Solid-state Nmr Spectroscopy ; Peptides; Alzheimers-disease; A-beta; Molecular-structure; Liquid Droplets; Peptide; Nmr; Fibrils; State; Identification; Validation
ISSN (print) / ISBN 1433-7851
e-ISSN 1521-3773
Quellenangaben Band: 59, Heft: 14, Seiten: 2-13 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Weinheim
Begutachtungsstatus Peer reviewed