Molecular Mechanism of Misfolding and Aggregation of Aβ(13–23)

Lovas, Sándor; Zhang, Yuliang; Yu, Junping; Lyubchenko, Yuri L.

doi:10.1021/jp402938p

Cited by 48 publications

(78 citation statements)

References 81 publications

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“…We speculate that the difference between the two types of dimers observed here is in the stability of b-sheet structure, the major contributor to a-Syn fibril formation. This interpretation is supported by our recent computational analysis of dimers formed by amyloid b (14-23) dimers, which showed the formation of two stable amyloid b dimers with different stabilities, as defined by b-sheet size (29). We also speculate that long-lived dimer species may be more neurotoxic compared to short-lived species.…”

Section: Conformational Dynamics Of A-syn Dimerssupporting

confidence: 79%

“…Evidence that misfolded dimers exhibit high stability led to the hypothesis that the formation of such dimers is the mechanism by which the misfolded state of amyloidogenic proteins is stabilized, suggesting that dimerization triggers the self-assembly process (11). Recent computational analyses confirmed this hypothesis (29). Molecular dynamics (MD) simulations played an important role in demonstrating that misfolded conformations did not occur in monomers but did appear in dimers, which remained stable over timescales of several hundreds of nanoseconds, whereas monomers changed their conformations in a few nanoseconds.…”

Section: Introductionmentioning

confidence: 99%

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Direct Detection of α-Synuclein Dimerization Dynamics: Single-Molecule Fluorescence Analysis

Krasnoslobodtsev

Zhang

et al. 2015

Biophysical Journal

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The aggregation of a-synuclein (a-Syn) is linked to Parkinson's disease. The mechanism of early aggregation steps and the effect of pathogenic single-point mutations remain elusive. We report here a single-molecule fluorescence study of a-Syn dimerization and the effect of mutations. Specific interactions between tethered fluorophore-free a-Syn monomers on a substrate and fluorophore-labeled monomers diffusing freely in solution were observed using total internal reflection fluorescence microscopy. The results showed that wild-type (WT) a-Syn dimers adopt two types of dimers. The lifetimes of type 1 and type 2 dimers were determined to be 197 5 3 ms and 3334 5 145 ms, respectively. All three of the mutations used, A30P, E46K, and A53T, increased the lifetime of type 1 dimer and enhanced the relative population of type 2 dimer, with type 1 dimer constituting the major fraction. The kinetic stability of type 1 dimers (expressed in terms of lifetime) followed the order A30P (693 5 14 ms) > E46K (292 5 5 ms) > A53T (226 5 6 ms) > WT (197 5 3 ms). Type 2 dimers, which are more stable, had lifetimes in the range of several seconds. The strongest effect, observed for the A30P mutant, resulted in a lifetime 3.5 times higher than observed for the WT type 1 dimer. This mutation also doubled the relative fraction of type 2 dimer. These data show that single-point mutations promote dimerization, and they suggest that the structural heterogeneity of a-Syn dimers could lead to different aggregation pathways.

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Section: Conformational Dynamics Of A-syn Dimerssupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Direct Detection of α-Synuclein Dimerization Dynamics: Single-Molecule Fluorescence Analysis

Krasnoslobodtsev

Zhang

et al. 2015

Biophysical Journal

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“…This conclusion is consistent with our very recent MD simulations for Aβ13-23 peptide showing that antiparallel β-sheet structure stabilized the peptide. 26 Interestingly, considerably less force (~60 pN) is applied for unfolding of the α-helical structure of T4 lysozyme 27 suggesting that Aβ42 dimers are more stable than dimers formed by misfolded α-helical structures of T4 lysozyme. The rupture forces for Aβ40 dimers are quite similar to those for Aβ42, indicating that the forces stabilizing both types of peptides are rather close.…”

Section: Discussionmentioning

confidence: 99%

Nanoprobing of misfolding and interactions of amyloid β 42 protein

Kim

Lyubchenko

2014

Nanomedicine: Nanotechnology, Biology and Medicine

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The assembly of amyloid β (Aβ) proteins into nanostructures is currently considered a major pathway of Alzheimer's disease development, but the molecular mechanisms of this self-assembly process remains unclear. Recently, we showed that single-molecule AFM force spectroscopy (SMFS) is capable of probing the dynamics and interaction between Aβ40 peptides, and these studies allowed us to shed new light on transiently existing Aβ40 misfolding states. In this study, we applied the same SMFS approach to characterize the misfolding of Aβ42 peptide, the most toxic Aβ alloform. The quantitative analysis of SMFS data demonstrated that Aβ interaction leads to the formation of dimers with a lifetime in the range of a second. Interaction via C-terminal segments prevailed at pH 7, but interaction within the peptide center prevailed at acidic pH levels. The difference in the misfolding properties for Aβ40 and Aβ42 peptides and the mechanisms of amyloid nanoassembly are discussed. KeywordsAmyloid beta; misfolding; single-molecule force spectroscopy; contour length; dimerization pathways Aberrant folding, misfolding, and aggregation of amyloid proteins are pathological hallmarks of a large class of neurodegenerative diseases. 1, 2 The assembly of amyloid β (Aβ) proteins in nanoaggeragtes is a ubiquitous phenomenon for a number of neurodegenerative disorders, including Alzheimer's disease (AD) (reviewed in 3, 4 ). Aβ proteins containing 42 and 40 residues (Aβ42 and Aβ40, respectively) are the major species, and Aβ42, which differs from Aβ40 by two extra C terminal residues (I41 and A42), has an elevated aggregation propensity and neurotoxicity compared to Aβ40. 5,6 Traditional © 2013 Elsevier Inc. All rights reserved. * Corresponding author: Yuri L. Lyubchenko, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, Phone: 402-559-1971; Fax: 402-559-9543, ylyubchenko@unmc. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. structural techniques, such as solid-state NMR, AFM, and electron microscopy, are widely used for their characterization of large aggregates, such as amyloid fibrils. However, these powerful techniques are not amenable to studies of oligomers that exist transiently and convert from one species to another, so novel approaches are needed for oligomers studies. The photocrosslinking method, developed for the stabilization of oligomers in Teplow lab 7 was instrumental in the spectroscopic characterization of Aβ42 oligomers 8 . It was shown that the transition from the monomer to the dimer is rapid and then proceeds gradually for h...

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“…14) Molecular dynamics (MD) simulation is a powerful tool for examining the dynamic motion of proteins and providing an explanation on the physicochemical properties of molecules. 15,16) Many computations have been performed to investigate the action of Aβ in an aqueous condition or in the presence of a lipid membrane. Some studies have focused on structural changes of Aβ peptides 17,18) while other studies have focused on the assembled formation of multiple Aβ peptides.…”

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confidence: 99%

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

2018

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Aggregation and complex formation of amyloid beta (Aβ) peptides on a neuronal cell membrane is a hallmark of neuro-disturbance diseases. In this work, we performed molecular dynamics (MD) simulations to investigate the initial stage of interactions of multiple Aβ 42 peptides on a GM1 ganglioside-containing membrane that mimics a micro-domain on the neuronal cell surface. Conformational changes of Aβs due to adhesion on the membrane and subsequent molecular interactions among the Aβs were monitored. It was suggested from results of the two 1.0 µs simulation trials that stable complexes of Aβ peptides were not rapidly generated but that a steady binding of two Aβs was gradually formed. Observation of two Aβs that will be a complex with steady binding revealed that one Aβ was bound to the membrane surface, while the other was attached to the first one without strong contact with the membrane. The motion of the first one was restricted and its conformational change was limited, with the basic side-chains of Arg5 and Lys28 working as anchors to hold the Aβ helix region on the membrane. In contrast, the second one had high flexibility and showed diversity in its conformation. The second Aβ can search for an energetically favorable binding position on the first one. A parallel β-sheet structure was formed between the C-terminal sides of the two Aβs. Ala30 was critically important to lead the stable β-sheet conformation at the C-terminal hydrophobic domains of Aβs. In the N-terminal sides, helix structures were kept in both Aβs.Key words amyloid beta peptide; molecular dynamics simulation; membrane surface; molecular interaction; conformational change; complex structure Aggregation of amyloid beta (Aβ)-peptides is closely linked to several neurodegeneration diseases including Alzheimer's disease (AD).1-3) Aβ is a small peptide consisting of typically 39-43 amino acid residues and it is a normal product of cellular metabolism from amyloid precursor protein (APP) due to the successive proteolytic action by β-and γ-secretases. 4,5) Aggregation and resultant transformation of Aβ peptides into insoluble misfolding proteins is a pathological hallmark of neurodegeneration diseases in the brain.4) The most commonly observed forms of toxic Aβs are comprised of 40 and/or 42 residues. Both of them show an affinity to a lipid membrane, but Aβ 42 (a.a. 1-42) is more likely to form amyloid fibrils. 6)This strong tendency of Aβ 42 to aggregate is related to two additional hydrophobic amino acids at its C-terminal end. 7)According to an in vivo study, 8) soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes more rapidly than non-toxic monomers and they were strongly bound to GM1-ganglioside on the cellular membranes. GM1 is likely to form a cluster on a membrane containing sphingomyelin (SM) and cholesterol (Chol). A GM1 cluster has a hydrophobic surface and a negatively charged area due to the condensation of glycans. Many in vitro studies have shown an acceleration of Aβ aggregation on lipid micro-d...

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Molecular Mechanism of Misfolding and Aggregation of Aβ(13–23)

Cited by 48 publications

References 81 publications

Direct Detection of α-Synuclein Dimerization Dynamics: Single-Molecule Fluorescence Analysis

Direct Detection of α-Synuclein Dimerization Dynamics: Single-Molecule Fluorescence Analysis

Nanoprobing of misfolding and interactions of amyloid β 42 protein

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

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