Structural Insight into IAPP‐Derived Amyloid Inhibitors and Their Mechanism of Action. (28th January 2020)

• Record Type: Journal Article
• Authors: Niu, Zheng; Prade, Elke; Malideli, Eleni; Hille, Kathleen; Jussupow, Alexander; Mideksa, Yonatan G.; Yan, Li‐Mei; Qian, Chen; Fleisch, Markus; Messias, Ana C.; Sarkar, Riddhiman; Sattler, Michael; Lamb, Don C.; Feige, Matthias J.; Camilloni, Carlo; Kapurniotu, Aphrodite; Reif, Bernd
• Is Part Of: Angewandte Chemie. Volume 132:Number 14(2020)
• Page Start: 5820
• Page End: 5830
• Publication Date: 2020-01-28
• Subjects: Amyloid-Bildung -- Amyloid-Inhibitoren -- Aβ -- Festkörper-NMR-Spektroskopie -- Peptide; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201914559
• Languages: English
• ISSNs: 0044-8249

Abstract

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. Abstract : ISM‐Inhibitoren bilden hochdynamische Assemblierungen und wechseln zwischen monomeren und oligomeren Zuständen. In beiden Zuständen hat das ISM‐Peptid eine β‐Schleifen‐artige Struktur, die eine geeignete Oberfläche für die Sequestrierung von Aβ40 im kolloidalen Zustand bietet. ISM‐Inhibitoren nutzen daher die durch Selbstorganisation erzeugt Multivalenz, um eine hohe Substrat‐Affinität zu erzielen.