Dataset Information

Islet Amyloid Polypeptide Promotes Amyloid-Beta Aggregation by Binding-Induced Helix-Unfolding of the Amyloidogenic Core.

ABSTRACT: Amyloid aggregation of amyloid-beta (A?) and islet amyloid polypeptide (IAPP) is associated with Alzheimer's disease (AD) and type-2 diabetes (T2D), respectively. With T2D being the risk factor for AD and the ability of IAPP to cross the blood-brain barrier, the coaggregation of A? and IAPP has been explored to understand the cross-talk between the two diseases. Recent studies demonstrated that soluble IAPP could significantly accelerate the aggregation of A? while preformed amyloids of IAPP were poor "seeds" for A? aggregation. Here, we apply all-atom discrete molecular dynamics simulations to investigate possible molecular mechanisms for the accelerated coaggregation of IAPP and A?42 comparing to A?42 aggregation alone, which was confirmed by the complementary thioflavin-T fluorescence assay. Our simulation results suggest that peptides in the mixture tend to form heterodimers as the first step toward their coaggregation. Strong interpeptide interactions with IAPP in the heterodimer shift the helical conformation of A?42 in its amyloidogenic central hydrophobic core, residues 16-22 (A?16-22), to the extended conformation ready to form ?-sheets. Our study suggests that the unfolding of A?16-22 helix contributes to the aggregation free-energy barrier and corresponds to the rate-limiting conformational change for A?42 aggregation. Therefore, we propose that soluble IAPP promotes the aggregation of A?42 by binding-induced conformational change of A?42 in its amyloidogenic core and thus reduced aggregation free-energy barrier.

SUBMITTER: Ge X

PROVIDER: S-EPMC5955824 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Publications

Islet Amyloid Polypeptide Promotes Amyloid-Beta Aggregation by Binding-Induced Helix-Unfolding of the Amyloidogenic Core.

Ge Xinwei X Yang Ye Y Sun Yunxiang Y Cao Weiguo W Ding Feng F

ACS chemical neuroscience 20180209 5

Amyloid aggregation of amyloid-beta (Aβ) and islet amyloid polypeptide (IAPP) is associated with Alzheimer's disease (AD) and type-2 diabetes (T2D), respectively. With T2D being the risk factor for AD and the ability of IAPP to cross the blood-brain barrier, the coaggregation of Aβ and IAPP has been explored to understand the cross-talk between the two diseases. Recent studies demonstrated that soluble IAPP could significantly accelerate the aggregation of Aβ while preformed amyloids of IAPP wer ...[more]

PMID: 29378116

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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.

Dataset Information

Islet Amyloid Polypeptide Promotes Amyloid-Beta Aggregation by Binding-Induced Helix-Unfolding of the Amyloidogenic Core.

Publications

Islet Amyloid Polypeptide Promotes Amyloid-Beta Aggregation by Binding-Induced Helix-Unfolding of the Amyloidogenic Core.

Similar Datasets

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