Helix Dipole and Membrane Electrostatics Delineate Conformational Transitions in the Self-Assembly of Amyloidogenic Peptides
The self-assembly of amyloidogenic peptides on membrane surfaces is associated with the death of neurons and β-cells in Alzheimer’s disease and type 2 diabetes, respectively. The early events of self-assembly in vivo are not known, but there is increasing evidence for the importance of the α-helix....
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| Published in: | Langmuir Vol. 36; no. 29; pp. 8389 - 8397 |
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| Main Authors: | , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
American Chemical Society
28-07-2020
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| Online Access: | Get full text |
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| Summary: | The self-assembly of amyloidogenic peptides on membrane surfaces is associated with the death of neurons and β-cells in Alzheimer’s disease and type 2 diabetes, respectively. The early events of self-assembly in vivo are not known, but there is increasing evidence for the importance of the α-helix. To test the hypothesis that electrostatic interactions involving the helix dipole play a key role in membrane-mediated peptide self-assembly, we studied IAPP[11–25(S20G)-NH2] (R11LANFLVHSGNNFGA25-NH2), which under certain conditions self-assembles in hydro to form β-sheet assemblies through an α-helix-containing intermediate. In the presence of small unilamellar vesicles composed solely of zwitterionic lipids, the peptide does not self-assemble presumably because of the absence of stabilizing electrostatic interactions between the membrane surface and the helix dipole. In the presence of vesicles composed solely of anionic lipids, the peptide forms a long-lived α-helix presumably stabilized by dipole–dipole interactions between adjacent helix dipoles. This helix represents a kinetic trap that inhibits β-sheet formation. Intriguingly, when the amount of anionic lipids was decreased to mimic the ratio of zwitterionic and anionic lipids in cells, the α-helix was short-lived and underwent an α-helix to β-sheet conformational transition. Our work suggests that the helix dipole and membrane electrostatics delineate the conformational transitions occurring along the self-assembly pathway to the amyloid. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author Contributions Q.Z. and S.N.C. performed all experiments and data analysis. All authors contributed to the writing of the manuscript and have given approval to its final version. |
| ISSN: | 0743-7463 1520-5827 |
| DOI: | 10.1021/acs.langmuir.0c00723 |