Structural Insight into IAPP-Derived Amyloid Inhibitors and Their Mechanism of Action
| العنوان: | Structural Insight into IAPP-Derived Amyloid Inhibitors and Their Mechanism of Action |
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| المؤلفون: | Aphrodite Kapurniotu, Ana C. Messias, Matthias J. Feige, Zheng Niu, Bernd Reif, Yonatan G. Mideksa, Chen Qian, Li-Mei Yan, Carlo Camilloni, Markus Fleisch, Don C. Lamb, Alexander Jussupow, Elke Prade, Michael Sattler, Kathleen Hille, Eleni Malideli, Riddhiman Sarkar |
| المصدر: | Angewandte Chemie (International Ed. in English) Adv. Mater. 59, 5820-5830 (2020) Angew. Chem.-Int. Edit. 59, 2-13 (2020) |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Amyloid, Peptide, amyloid formation, Molecular Dynamics Simulation, 010402 general chemistry, 01 natural sciences, Catalysis, Fluorescence spectroscopy, Substrate Specificity, medicine, Molecule, ddc:630, Amino Acid Sequence, Nuclear Magnetic Resonance, Biomolecular, solid-state NMR spectroscopy, Research Articles, Aβ, chemistry.chemical_classification, Amyloid-bildung, Amyloid-inhibitoren, Festkörper-nmr-spektroskopie, Amyloid beta-Peptides, 010405 organic chemistry, Chemistry, Amyloid Formation, Amyloid Inhibitors, A Beta, Solid-state Nmr Spectroscopy, Peptides, General Medicine, General Chemistry, Nuclear magnetic resonance spectroscopy, Peptide Fragments, 0104 chemical sciences, ddc, Islet Amyloid Polypeptide, Mechanism of action, Microscopy, Fluorescence, Biophysics, peptides, Aβ amyloid, medicine.symptom, Function (biology), Research Article |
| الوصف: | 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. ISM inhibitors are highly dynamic assemblies and exchange between monomeric and high‐molecular‐weight states. In both states, the ISM peptide adopts a β‐loop‐like structure that provides a suitable surface for sequestration of Aβ40 in the colloidal state. ISM inhibitors thus exploit multivalency by self‐association to yield high substrate avidity. |
| وصف الملف: | application/pdf |
| تدمد: | 1521-3773 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6e5bac7e5a286d7746d16df0f3a9ae13 https://pubmed.ncbi.nlm.nih.gov/31863711 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6e5bac7e5a286d7746d16df0f3a9ae13 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15213773 |
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