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Oligomerization Alters Binding Affinity Between Amyloid Beta and a Modulator of Peptide Aggregation.

ABSTRACT: The soluble oligomeric form of the amyloid beta (A?) peptide is the major causative agent in the molecular pathogenesis of Alzheimer's disease (AD). We have previously developed a pyrroline-nitroxyl fluorene compound (SLF) that blocks the toxicity of A?. Here we introduce the multi-parametric surface plasmon resonance (MP-SPR) approach to quantify SLF binding and effect on the self-association of the peptide via a label-free, real-time approach. Kinetic analysis of SLF binding to A? and measurements of layer thickness alterations inform on the mechanism underlying the ability of SLF to inhibit A? toxicity and its progression towards larger oligomeric assemblies. Depending on the oligomeric state of A?, distinct binding affinities for SLF are revealed. The A? monomer and dimer uniquely possess sub-nanomolar affinity for SLF via a non-specific mode of binding. SLF binding is weaker in oligomeric A?, which displays an affinity for SLF on the order of 100 ?M. To complement these experiments we carried out molecular docking and molecular dynamics simulations to explore how SLF interacts with the A? peptide. The MP-SPR results together with in silico modeling provide affinity data for the SLF-A? interaction and allow us to develop a new general method for examining protein aggregation.

SUBMITTER: Hilt S

PROVIDER: S-EPMC6130836 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Oligomerization Alters Binding Affinity Between Amyloid Beta and a Modulator of Peptide Aggregation.

Hilt Silvia S Rojalin Tatu T Viitala Tapani T Koivuniemi Artturi A Bunker Alex A Hogiu Sebastian Wachsmann SW Kálai Tamás T Hideg Kálmán K Yliperttula Marjo M Voss John C JC

The journal of physical chemistry. C, Nanomaterials and interfaces 20171010 43

The soluble oligomeric form of the amyloid beta (Aβ) peptide is the major causative agent in the molecular pathogenesis of Alzheimer's disease (AD). We have previously developed a pyrroline-nitroxyl fluorene compound (SLF) that blocks the toxicity of Aβ. Here we introduce the multi-parametric surface plasmon resonance (MP-SPR) approach to quantify SLF binding and effect on the self-association of the peptide via a label-free, real-time approach. Kinetic analysis of SLF binding to Aβ and measurem ...[more]

PMID: 30214656

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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

Oligomerization Alters Binding Affinity Between Amyloid Beta and a Modulator of Peptide Aggregation.

Publications

Oligomerization Alters Binding Affinity Between Amyloid Beta and a Modulator of Peptide Aggregation.

Similar Datasets

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