Effect of the beta‐sheet‐breaker peptide LPFFD on oriented network of amyloid β25‐35 fibrils

Murvai, Ünige; Soós, Katalin; Penke, Botond; Kellermayer, Miklós

doi:10.1002/jmr.1113

Cited by 10 publications

(6 citation statements)

References 21 publications

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“…7 D). Our results are analogous to the peeling of amyloid protofilaments away from the bundles by dismantling side-by-side associations (see, e.g., Kellermayer and colleagues (54)(55)(56)), but in our case, the fibrils are embedded in a gel matrix with junction zones of varying strengths. Note that long force steps can arise due to desorption of fibrils from the substrate in a train conformation (see, e.g., (57)(58)(59)(60)(61)).…”

Section: Hierarchical Force Staircases As a Mechanical Signature Of The Gel Networksupporting

confidence: 77%

Self-Assembly of Polysaccharides Gives Rise to Distinct Mechanical Signatures in Marine Gels

Pletikapić

Lannon

Murvai

et al. 2014

Biophysical Journal

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Marine-gel biopolymers were recently visualized at the molecular level using atomic force microscopy (AFM) to reveal fine fibril-forming networks with low to high degrees of cross-linking. In this work, we use force spectroscopy to quantify the intra- and intermolecular forces within the marine-gel network. Combining force measurements, AFM imaging, and the known chemical composition of marine gels allows us to identify the microscopic origins of distinct mechanical responses. At the single-fibril level, we uncover force-extension curves that resemble those of individual polysaccharide fibrils. They exhibit entropic elasticity followed by extensions associated with chair-to-boat transitions specific to the type of polysaccharide at high forces. Surprisingly, a low degree of cross-linking leads to sawtooth patterns that we attribute to the unraveling of polysaccharide entanglements. At a high degree of cross-linking, we observe force plateaus that arise from unzipping, as well as unwinding, of helical bundles. Finally, the complex 3D network structure gives rise to force staircases of increasing height that correspond to the hierarchical peeling of fibrils away from the junction zones. In addition, we show that these diverse mechanical responses also arise in reconstituted polysaccharide gels, which highlights their dominant role in the mechanical architecture of marine gels.

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Section: Hierarchical Force Staircases As a Mechanical Signature Of The Gel Networksupporting

confidence: 77%

Self-Assembly of Polysaccharides Gives Rise to Distinct Mechanical Signatures in Marine Gels

Pletikapić

Lannon

Murvai

et al. 2014

Biophysical Journal

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“…Inspired by the way biological systems harness multivalent molecular interactions, 25−27 mPPCs consist of a hydrophilic polymer backbone bearing multiple copies of the "β-breaker" peptide LPFFD. 28,29 In previous works, it was shown that mPPCs can modulate both the growth and stability of amyloid, inhibiting the formation of Aβ 40 fibrils 13,23 and breaking down preformed Aβ 40 fibrils into sub-100-nm structures. 16 By virtue of their multivalency, mPPCs achieve significantly higher inhibition and disassembly efficacy than corresponding amounts of monomeric LPFFD.…”

Section: ■ Introductionmentioning

confidence: 99%

Polymer−Peptide Conjugates Convert Amyloid into Protein Nanobundles through Fragmentation and Lateral Association

Smith

Barclay

et al. 2019

ACS Appl. Nano Mater.

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The assembly of proteins into amyloid fibrils has become linked not only with the progression of myriad human diseases, but also important biological functions. Understanding and controlling the formation, structure, and stability of amyloid fibrils is therefore a major scientific goal. Here we utilize electron microscopy-based approaches combined with quantitative statistical analysis to show how recently developed kind of amyloid modulators-multivalent polymer-peptide conjugates (mPPCs)-can be applied to control the structure and stability of amyloid fibrils. In doing so, we demonstrate that mPPCs are able to convert 40-residue amyloid beta fibrils into ordered nanostructures through a combination of fragmentation and bundling. Fragmentation is shown to be consistent with a model where the rate constant of fibril breakage is independent of the fibril length, suggesting a local and specific interaction between fibrils and mPPCs. Subsequent bundling, which was previously not observed, leads to the formation of sheet-like nanostructures which are surprisingly much more uniform than the starting fibrils. These nanostructures have dimensions independent of the molecular weight of the mPPC and retain the molecular-level ordering of the starting amyloid fibrils. Collectively, we reveal quantitative and nanoscopic understanding of how mPPCs can be applied to control amyloid structure and stability, and demonstrate approaches to elucidate nanoscale amyloid phase behavior in the presence of functional macromolecules and other modulators.

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“…Currently, several types of inhibitors that target amyloid aggregation are under development, including small molecule inhibitors, peptides, nanoparticles, antibodies, and proteins . Among them, peptides and peptidomimetics have been extensively studied for their specific interactions with Aβ .…”

Section: Introductionmentioning

confidence: 99%

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Zhang

Dong

et al. 2018

J of Molecular Recognition

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Dysfunctional accumulation of amyloid β-protein (Aβ) mediated by Cu exhibits higher neurotoxicity and accelerates the progress of Alzheimer's disease, so inhibition of Cu -mediated Aβ aggregation and cytotoxicity has been considered as a therapeutic strategy for the disease. Herein, a nonapeptide was designed by linking HH to the C-terminus of a peptide inhibitor of Aβ aggregation, LVFFARK (LK7). We found that the nonapeptide, LK7-HH, possessed dual functionality, including enhanced inhibition capability on Aβ aggregation as compared to LK7, and chelating Cu with a dissociation constant of 5.50 μM. This enabled LK7-HH to arrest the generation of reactive oxygen species catalyzed by Cu or Cu -Aβ complex, and to inhibit Cu -induced Aβ aggregation. Moreover, in contrast with the cytotoxicity of LK7 aggregates, LK7-HH was biocompatible because HH conjugation made its aggregation behavior different from LK7. Thus, LK7-HH efficiently suppressed Cu -mediated Aβ aggregation and cytotoxicity. An equimolar concentration of LK7-HH increased cell viability from 50% to 90% when treating Aβ -Cu complexes. The results provided insights into the roles of HH in enhancing the inhibition of Aβ and Cu -induced Aβ aggregations, in eliminating Cu -induced cytotoxicities by arresting generation of reactive oxygen species, and in making the peptide biocompatible. Therefore, this work would contribute to the design of potent peptide-based inhibitors of Cu -mediated Aβ aggregation and cytotoxicity.

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Effect of the beta‐sheet‐breaker peptide LPFFD on oriented network of amyloid β25‐35 fibrils

Cited by 10 publications

References 21 publications

Self-Assembly of Polysaccharides Gives Rise to Distinct Mechanical Signatures in Marine Gels

Self-Assembly of Polysaccharides Gives Rise to Distinct Mechanical Signatures in Marine Gels

Polymer−Peptide Conjugates Convert Amyloid into Protein Nanobundles through Fragmentation and Lateral Association

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

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Effect of the beta‐sheet‐breaker peptide LPFFD on oriented network of amyloid β25‐35 fibrils

Cited by 10 publications

References 21 publications

Self-Assembly of Polysaccharides Gives Rise to Distinct Mechanical Signatures in Marine Gels

Self-Assembly of Polysaccharides Gives Rise to Distinct Mechanical Signatures in Marine Gels

Polymer−Peptide Conjugates Convert Amyloid into Protein Nanobundles through Fragmentation and Lateral Association

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu2+‐mediated amyloid β‐protein aggregation and cytotoxicity

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Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity