Lipid domain boundary triggers membrane damage and protein folding of human islet amyloid polypeptide in the early pathogenesis of amyloid diseases

The misfolding and self-aggregation of human Islet Amyloid Polypeptide (hIAPP) are linked to the onset of type 2 diabetes (T2D). However, the mechanism of how the disordered hIAPP aggregates trigger membrane damage leading to the loss of Islet cells in T2D is unknown. Using coarse-grained (CG) and a...

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Bibliographic Details
Published in:Biophysical chemistry 2023-05, Vol.296, p.106993-106993, Article 106993
Main Authors: Lewis, Amber, Pham, Thuong, Nguyen, Ngoc, Graf, Angela, Cheng, Kwan H.
Format: Article
Language:English
Subjects:
Amyloid - chemistry
Amyloidosis - metabolism
Cell Membrane - chemistry
Diabetes
Diabetes Mellitus, Type 2 - metabolism
Humans
Intrinsically disordered protein
Islet Amyloid Polypeptide - chemistry
Lipids
Membrane biophysics
Membrane protein
Membrane structure
Molecular dynamics
Protein Folding
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Summary:The misfolding and self-aggregation of human Islet Amyloid Polypeptide (hIAPP) are linked to the onset of type 2 diabetes (T2D). However, the mechanism of how the disordered hIAPP aggregates trigger membrane damage leading to the loss of Islet cells in T2D is unknown. Using coarse-grained (CG) and all-atom (AA) molecular dynamics simulations, we have investigated the membrane-disruption behaviors of hIAPP oligomers on the phase-separated lipid nanodomains that mimic the highly heterogeneous lipid raft structures of cell membranes. Our results revealed that hIAPP oligomers preferentially bind to the liquid-ordered and liquid-disordered domain boundary around two hydrophobic residues at L16 and I26, and lipid acyl chain order disruption and beta-sheet formation occur upon hIAPP binding to the membrane surface. We propose that the lipid order disruption and surface-induced beta-sheet formation on the lipid domain boundary represent the early molecular events of membrane damage associated with the early pathogenesis of T2D. [Display omitted] •Designed phase-separated lipid rafts.•Constructed hIAPP oligomers from monomer to tetramer.•hIAPP oligomers bound to interfacial Lod lipid domains and disrupted membrane structures.•Observed surface-induced disorder-to-order transition of hIAPP oligomers.•Membrane disruption and beta-sheet formation are early events of hIAPP aggregation pathway that leads to type 2 diabetes.
ISSN:0301-4622
1873-4200
DOI:10.1016/j.bpc.2023.106993