Self-assembly of the full-length amyloid Aβ42 protein in dimers

Zhang, Yuliang; Hashemi, Mohtadin; Lv, Zhengjian; Lyubchenko, Yuri L.

doi:10.1039/c6nr06850b

Cited by 47 publications

(83 citation statements)

References 70 publications

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“…This in silico study showed the stability of an Aβ1-42 dimer that interacted with a long filament, which is consistent with the in vitro experimental study where fibrils facilitated the nucleation of Aβ1-42 peptides, simultaneously using two monomers in the initial step of oligomer formation [95]. However, Zahng et al reported that the probability that Aβ1-42 dimers exist in a U and S shape is very low [96]. …”

Section: Introductionsupporting

confidence: 82%

Recent Advances by In Silico and In Vitro Studies of Amyloid-β 1-42 Fibril Depicted a S-Shape Conformation

Acosta

Chimal-Vega

Correa-Basurto

et al. 2018

IJMS

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The amyloid-β 1-42 (Aβ1-42) peptide is produced by proteolytic cleavage of the amyloid precursor protein (APP) by sequential reactions that are catalyzed by γ and β secretases. Aβ1-42, together with the Tau protein are two principal hallmarks of Alzheimer’s disease (AD) that are related to disease genesis and progression. Aβ1-42 possesses a higher aggregation propensity, and it is able to form fibrils via nucleated fibril formation. To date, there are compounds available that prevent Aβ1-42 aggregation, but none have been successful in clinical trials, possibly because the Aβ1-42 structure and aggregation mechanisms are not thoroughly understood. New molecules have been designed, employing knowledge of the Aβ1-42 structure and are based on preventing or breaking the ionic interactions that have been proposed for formation of the Aβ1-42 fibril U-shaped structure. Recently, a new Aβ1-42 fibril S-shaped structure was reported that, together with its aggregation and catalytic properties, could be helpful in the design of new inhibitor molecules. Therefore, in silico and in vitro methods have been employed to analyze the Aβ1-42 fibril S-shaped structure and its aggregation to obtain more accurate Aβ1-42 oligomerization data for the design and evaluation of new molecules that can prevent the fibrillation process.

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Section: Introductionsupporting

confidence: 82%

Recent Advances by In Silico and In Vitro Studies of Amyloid-β 1-42 Fibril Depicted a S-Shape Conformation

Acosta

Chimal-Vega

Correa-Basurto

et al. 2018

IJMS

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“…These values run in contrast with (i) previous OPLS MD simulation starting from multiple conformations with 0.9% of helix and 6.6% of β -strand, 20 (ii) recent standard and accelerated MD trajectories using AMBER99sb-ildn/TIP3P 24 with 4% of helix and 5% of β -strand, 22 vs 6% and 24% with our F99 contents, and (iii) to a lesser extent to extensive DMD simulations of A β 42 peptides coupled to an implicit solvent four-bead CG model with 0% of helix and 15.7% of β -strand. 52 …”

Section: Discussionmentioning

confidence: 72%

High-Resolution Structures of the Amyloid-β 1–42 Dimers from the Comparison of Four Atomistic Force Fields

2017

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The dimer of the amyloid-β peptide Aβ of 42 residues is the smallest toxic species in Alzheimer’s disease, but its equilibrium structures are unknown. Here we determined the equilibrium ensembles generated by the four atomistic OPLS-AA, CHARMM22*, AMBER99sb-ildn, and AMBERsb14 force fields with the TIP3P water model. On the basis of 144 µs replica exchange molecular dynamics simulations (with 750 ns per replica), we find that the four force fields lead to random coil ensembles with calculated cross-collision sections, hydrodynamics properties, and small-angle X-ray scattering profiles independent of the force field. There are, however, marked differences in secondary structure, with the AMBERsb14 and CHARMM22* ensembles overestimating the CD-derived helix content, and the OPLS-AA and AMBER99sb-ildn secondary structure contents in agreement with CD data. Also the intramolecular beta-hairpin content spanning residues 17–21 and 30–36 varies between 1.5% and 13%. Overall, there are significant differences in tertiary and quaternary conformations among all force fields, and the key finding, irrespective of the force field, is that the dimer is stabilized by nonspecific interactions, explaining therefore its possible transient binding to multiple cellular partners and, in part, its toxicity.

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“…3 and Supplementary Movie 2 reveal a number of features of the dimer assembly process. First, in contrast to a slow Aβ42 dimer formation in solution 14 , the dimer on the surface assembles rapidly, after ~23 ns of simulation ( Fig. 3a).…”

Section: Resultsmentioning

confidence: 98%

“…Figure 2a shows a few snapshots illustrating the structural change of Aβ monomers induced by its interaction with POPC bilayer. The initial conformation of Aβ monomer (snapshot (i)), taken from our recent paper 14 , has essentially random coiled configuration. However, already after ~ 500 ns, two β-strands appear at the C-and N-termini of the molecule (snapshot (ii)).…”

Section: Resultsmentioning

confidence: 99%

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Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

Banerjee

Hashemi

Zagorski

et al. 2019

Preprint

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The assembly of polypeptides and proteins into nanoscale aggregates is a phenomenon observed in a vast majority of proteins. Importantly, aggregation of amyloid β (Aβ) proteins is considered as a major cause for the development of Alzheimer's disease. The process depends on various conditions and typical test-tube experiments require high protein concentration that complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here we demonstrate that Aβ42 monomers at the membrane bilayer are capable of self-assembling into aggregates at physiologically low concentrations, and the membrane in this aggregation process plays a role of a catalyst. We applied all-atom molecular dynamics to demonstrate that the interaction with the membrane surface dramatically changes the conformation of Aβ42 protein. As a result, the misfolded Aβ42 rapidly assembles into dimers, trimers and tetramers, so the on-surface aggregation is the mechanism by which amyloid oligomers are produced and spread.Self-assembly is a widely spread phenomenon in biology and the assembly of proteins into nanoaggerates with various morphologies is a phenomenon of a special attention for decades. Evidence strongly suggests that the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), is due to the self-assembly of amyloid β (Aβ) and α-synuclein oligomers, respectively 1 . These oligomers appear to disrupt the cell homeostasis, by various mechanisms, resulting in the early stages of neurodegenerative diseases 2-4 . The amyloid cascade hypothesis (ACH) 5 is the major model that describes the pathology of AD and other neurodegenerative diseases 5-9 . However, several orders higher concentrations of Aβ compared with that found in vivo are required for the spontaneous aggregation of Aβ, which challenges the validity of ACH. We have discovered that amyloid proteins and peptides are capable of assembling into aggregates at nanomolar concentration range if the process occurs at the surface-liquid interface 10,11 . In the present study, we monitored the aggregation of Aβ42 at its physiologically relevant low concentration (10 nM) on supported lipid bilayers (SLBs) formed by 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-snglycero-3-phospho-L-serine (POPS).Direct time-lapse AFM imaging revealed Aβ42 aggregation on the bilayer surfaces, while no self-assembly of Aβ42 was detected in bulk solution. We performed computational modeling of the aggregation process on the membrane surfaces to demonstrate that interaction of Aβ42 dramatically changes the conformation of Aβ42 monomers. Moreover, membrane-bound Aβ42 proteins trigger the assembly of dimers, trimers, and tetramers, propagating the misfolded states of the Aβ42 molecules. Thus, interaction with membranes results in the transition of Aβ42 into the aggregation-prone, misfolded conformations. Such conformations have not been reported in

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Self-assembly of the full-length amyloid Aβ42 protein in dimers

Cited by 47 publications

References 70 publications

Recent Advances by In Silico and In Vitro Studies of Amyloid-β 1-42 Fibril Depicted a S-Shape Conformation

Recent Advances by In Silico and In Vitro Studies of Amyloid-β 1-42 Fibril Depicted a S-Shape Conformation

High-Resolution Structures of the Amyloid-β 1–42 Dimers from the Comparison of Four Atomistic Force Fields

Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

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