Revealing a Dual Role of Ganglioside Lipids in the Aggregation of Membrane-Associated Islet Amyloid Polypeptide
Amyloid formation of the human islet amyloid polypeptide (hIAPP) correlates with a loss of insulin-producing beta cells in patients with type II diabetes mellitus. In this study, we investigated the binding of hIAPP to bilayers consisting of ganglioside lipids and dioleoylphosphatidylcholine (DOPC), which is a physiologically relevant lipid species for pancreatic beta cell-associated aggregation. The membrane interactions are studied computationally using a combination of coarse-grained, umbrella sampling, and atomistic molecular dynamics simulations. Herein, we demonstrate how the hIAPP peptides accumulate in the areas with a high content of ganglioside lipids. We have characterized two distinct binding modes of hIAPP on ganglioside-rich membranes, with both binding modes formed due to electrostatic interaction between the cationic peptides and the anionic ganglioside headgroup. We observed that binding in the ganglioside headgroup region induced conformational changes of the peptide towards an aggregation prone conformation, rich in β-strands. In contrast, the binding of hIAPP near the ganglioside-enriched areas mobilizes the peptide, preventing it from conformational changes and potentially shields it from interactions with other peptides. This suggests a dual role of ganglioside lipids, affecting the aggregation of hIAPP by either accelerating or inhibiting amyloid formation depending on the membrane binding and the ganglioside concentration.
KeywordsAmyloid Lipid membranes Misfolding Diabetes Aggregation
Computations were performed at the Grendel cluster of the Centre for Scientific Computing Aarhus (CSCAA), Aarhus University and at the Abacus 2.0 of the DeIC National HPC Centre, University of Southern Denmark. Dr. Xavier Periole is thanked for fruitful discussions.
Funding was provided by Lundbeckfonden (Grant No. R191-2015-827) and by Sino-Danish Center.
Compliance with Ethical Standards
Conflict of interest
The authors declare no conflicts of interest.
Research Involving Human and Animal Participants
This article does not contain any studies with human participants or animals performed by any of the authors.
All co-authors have agreed to submission and we state that the results have neither previously been made publicly available, nor are they under consideration for publication elsewhere.
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