Dataset Information

Adsorption and Orientation of Human Islet Amyloid Polypeptide (hIAPP) Monomer at Anionic Lipid Bilayers: Implications for Membrane-Mediated Aggregation.

ABSTRACT: Protein misfolding and aggregation cause serious degenerative diseases, such as Alzheimer's and type II diabetes. Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in the pancreas of type II diabetic patients. Increasing evidence suggests that ?-cell death is related to the interaction of hIAPP with the cellular membrane, which accelerates peptide aggregation. In this study, as a first step towards understanding the membrane-mediated hIAPP aggregation, we investigate the atomic details of the initial step of hIAPP-membrane interaction, including the adsorption orientation and conformation of hIAPP monomer at an anionic POPG lipid bilayer by performing all-atom molecular dynamics simulations. We found that hIAPP monomer is quickly adsorbed to bilayer surface, and the adsorption is initiated from the N-terminal residues driven by strong electrostatic interactions of the positively-charged residues K1 and R11 with negatively-charged lipid headgroups. hIAPP binds parallel to the lipid bilayer surface as a stable helix through residues 7-22, consistent with previous experimental study. Remarkably, different simulations lead to the same binding orientation stabilized by electrostatic and H-bonding interactions, with residues R11, F15 and S19 oriented towards membrane and hydrophobic residues L12, A13, L16 and V17 exposed to solvent. Implications for membrane-mediated hIAPP aggregation are discussed.

SUBMITTER: Jia Y

PROVIDER: S-EPMC3634446 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Adsorption and Orientation of Human Islet Amyloid Polypeptide (hIAPP) Monomer at Anionic Lipid Bilayers: Implications for Membrane-Mediated Aggregation.

Jia Yan Y Qian Zhenyu Z Zhang Yun Y Wei Guanghong G

International journal of molecular sciences 20130319 3

Protein misfolding and aggregation cause serious degenerative diseases, such as Alzheimer's and type II diabetes. Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in the pancreas of type II diabetic patients. Increasing evidence suggests that β-cell death is related to the interaction of hIAPP with the cellular membrane, which accelerates peptide aggregation. In this study, as a first step towards understanding the membrane-mediated hIAPP aggregation, we i ...[more]

PMID: 23519103

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Project description:Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1-42) as a successful strategy to inhibit its aggregation involved in Alzheimer's disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.

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

Adsorption and Orientation of Human Islet Amyloid Polypeptide (hIAPP) Monomer at Anionic Lipid Bilayers: Implications for Membrane-Mediated Aggregation.

Publications

Adsorption and Orientation of Human Islet Amyloid Polypeptide (hIAPP) Monomer at Anionic Lipid Bilayers: Implications for Membrane-Mediated Aggregation.

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