Dataset Information

Lipid Modulation in the Formation of ?-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on ?-Cell Homeostasis.

ABSTRACT: Human islet amyloid polypeptide (hIAPP) corresponds to a 37-residue hormone present in insulin granules that maintains a high propensity to form ?-sheet structures during co-secretion with insulin. Previously, employing a biomimetic approach, we proposed a panel of optimized IAPP sequences with only one residue substitution that shows the capability to reduce amyloidogenesis. Taking into account that specific membrane lipids have been considered as a key factor in the induction of cytotoxicity, in this study, following the same design strategy, we characterize the effect of a series of lipids upon several polypeptide domains that show the highest aggregation propensity. The characterization of the C-native segment of hIAPP (residues F23-Y37), together with novel variants F23R and I26A allowed us to demonstrate an effect upon the formation of ?-sheet structures. Our results suggest that zwitterionic phospholipids promote adsorption of the C-native segments at the lipid-interface and ?-sheet formation with the exception of the F23R variant. Moreover, the presence of cholesterol did not modify this behavior, and the ?-sheet structural transitions were not registered when the N-terminal domain of hIAPP (K1-S20) was characterized. Considering that insulin granules are enriched in phosphatidylserine (PS), the property of lipid vesicles containing negatively charged lipids was also evaluated. We found that these types of lipids promote ?-sheet conformational transitions in both the C-native segment and the new variants. Furthermore, these PS/peptides arrangements are internalized in Langerhans islet ?-cells, localized in the endoplasmic reticulum, and trigger critical pathways such as unfolded protein response (UPR), affecting insulin secretion. Since this phenomenon was associated with the presence of cytotoxicity on Langerhans islet ?-cells, it can be concluded that the anionic lipid environment and degree of solvation are critical conditions for the stability of segments with the propensity to form ?-sheet structures, a situation that will eventually affect the structural characteristics and stability of IAPP within insulin granules, thus modifying the insulin secretion.

SUBMITTER: Martinez-Navarro I

PROVIDER: S-EPMC7563882 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis.

Martínez-Navarro Israel I Díaz-Molina Raúl R Pulido-Capiz Angel A Mas-Oliva Jaime J Luna-Reyes Ismael I Rodríguez-Velázquez Eustolia E Rivero Ignacio A IA Ramos-Ibarra Marco A MA Alatorre-Meda Manuel M García-González Victor V

Biomolecules 20200819 9

Human islet amyloid polypeptide (hIAPP) corresponds to a 37-residue hormone present in insulin granules that maintains a high propensity to form β-sheet structures during co-secretion with insulin. Previously, employing a biomimetic approach, we proposed a panel of optimized IAPP sequences with only one residue substitution that shows the capability to reduce amyloidogenesis. Taking into account that specific membrane lipids have been considered as a key factor in the induction of cytotoxicity, ...[more]

PMID: 32824918

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Project description:A leading hypothesis for the decimation of insulin-producing ?-cells in type 2 diabetes attributes the cause to islet amyloid polypeptide (IAPP) for its deleterious effects on the cell membranes. This idea has produced extensive investigations on human IAPP (hIAPP) and its interactions with lipid bilayers. However, it is still difficult to correlate the peptide-lipid interactions with its effects on islet cells in culture. The hIAPP fibrils have been shown to interact with lipids and damage lipid bilayers, but appear to have no effect on islet cells in culture. Thus, a modified amyloid hypothesis assumes that the toxicity is caused by hIAPP oligomers, which are not preamyloid fibrils or protofibrils. However, so far such oligomers have not been isolated or identified. The hIAPP monomers also bind to lipid bilayers, but the mode of interaction is not clear. Here, we performed two types of experiments that, to our knowledge, have not been done before. We used x-ray diffraction, in conjunction with circular dichroism measurement, to reveal the location of the peptide bound to a lipid bilayer. We also investigated the effects of hIAPP on giant unilamellar vesicles at various peptide concentrations. We obtained the following qualitative results. Monomeric hIAPP binds within the headgroup region and expands the membrane area of a lipid bilayer. At low concentrations, such binding causes no leakage or damage to the lipid bilayer. At high concentrations, the bound peptides transform to ?-aggregates. The aggregates exit the headgroup region and bind to the surface of lipid bilayers. The damage by the surface bound ?-aggregates depends on the aggregation size. The initial aggregation extracts lipid molecules, which probably causes ion permeation, but no molecular leakage. However, the initial ?-aggregates serve as the seed for larger fibrils, in the manner of the Jarrett-Lansbury seeded-polymerization model, that eventually disintegrate lipid bilayers by electrostatic and hydrophobic interactions.

Dataset Information

Lipid Modulation in the Formation of ?-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on ?-Cell Homeostasis.

Publications

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis.

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