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Nucleation of ?-rich oligomers and ?-barrels in the early aggregation of human islet amyloid polypeptide.

ABSTRACT: The self-assembly of human islet amyloid polypeptide (hIAPP) into ?-sheet rich amyloid aggregates is associated with pancreatic ?-cell death in type 2 diabetes (T2D). Prior experimental studies of hIAPP aggregation reported the early accumulation of ?-helical intermediates before the rapid conversion into ?-sheet rich amyloid fibrils, as also corroborated by our experimental characterizations with transmission electron microscopy and Fourier transform infrared spectroscopy. Although increasing evidence suggests that small oligomers populating early hIAPP aggregation play crucial roles in cytotoxicity, structures of these oligomer intermediates and their conformational conversions remain unknown, hindering our understanding of T2D disease mechanism and therapeutic design targeting these early aggregation species. We further applied large-scale discrete molecule dynamics simulations to investigate the oligomerization of full-length hIAPP, employing multiple molecular systems of increasing number of peptides. We found that the oligomerization process was dynamic, involving frequent inter-oligomeric exchanges. On average, oligomers had more ?-helices than ?-sheets, consistent with ensemble-based experimental measurements. However, in ~4-6% independent simulations, ?-rich oligomers expected as the fibrillization intermediates were observed, especially in the pentamer and hexamer simulations. These ?-rich oligomers could adopt ?-barrel conformations, recently postulated to be the toxic oligomer species but only observed computationally in the aggregates of short amyloid protein fragments. Free-energy analysis revealed high energies of these ?-rich oligomers, supporting the nucleated conformational changes of oligomers in amyloid aggregation. ?-barrel oligomers of full-length hIAPP with well-defined three-dimensional structures may play an important pathological role in T2D etiology and may be a therapeutic target for the disease.

SUBMITTER: Sun Y

PROVIDER: S-EPMC6310638 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Nucleation of β-rich oligomers and β-barrels in the early aggregation of human islet amyloid polypeptide.

Sun Yunxiang Y Kakinen Aleksandr A Xing Yanting Y Pilkington Emily H EH Davis Thomas P TP Ke Pu Chun PC Ding Feng F

Biochimica et biophysica acta. Molecular basis of disease 20181128 2

The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet rich amyloid aggregates is associated with pancreatic β-cell death in type 2 diabetes (T2D). Prior experimental studies of hIAPP aggregation reported the early accumulation of α-helical intermediates before the rapid conversion into β-sheet rich amyloid fibrils, as also corroborated by our experimental characterizations with transmission electron microscopy and Fourier transform infrared spectroscopy. Although increasing e ...[more]

PMID: 30502402

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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

Nucleation of ?-rich oligomers and ?-barrels in the early aggregation of human islet amyloid polypeptide.

Publications

Nucleation of β-rich oligomers and β-barrels in the early aggregation of human islet amyloid polypeptide.

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