| Autor: |
Ngoc Nguyen, Amber Lewis, Thuong Pham, Donald Sikazwe, Kwan H. Cheng |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Molecules, Vol 28, Iss 10, p 4191 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1420-3049 |
| DOI: |
10.3390/molecules28104191 |
| Popis: |
The aggregation of human Islet Amyloid Polypeptide (hIAPP) on cell membranes is linked to amyloid diseases. However, the physio-chemical mechanisms of how these hIAPP aggregates trigger membrane damage are unclear. Using coarse-grained and all-atom molecular dynamics simulations, we investigated the role of lipid nanodomains in the presence or absence of anionic lipids, phosphatidylserine (PS), and a ganglioside (GM1), in the membrane disruption and protein folding behaviors of hIAPP aggregates on phase-separated raft membranes. Our raft membranes contain liquid-ordered (Lo), liquid-disordered (Ld), mixed Lo/Ld (Lod), PS-cluster, and GM1-cluster nanosized domains. We observed that hIAPP aggregates bound to the Lod domain in the absence of anionic lipids, but also to the GM1-cluster- and PS-cluster-containing domains, with stronger affinity in the presence of anionic lipids. We discovered that L16 and I26 are the lipid anchoring residues of hIAPP binding to the Lod and PS-cluster domains. Finally, significant lipid acyl chain order disruption in the annular lipid shells surrounding the membrane-bound hIAPP aggregates and protein folding, particularly beta-sheet formation, in larger protein aggregates were evident. We propose that the interactions of hIAPP and both non-anionic and anionic lipid nanodomains represent key molecular events of membrane damage associated with the pathogenesis of amyloid diseases. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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