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Antibodies and Protein Engineering 2017: Nano-assembly of amyloid β peptide: Role of the hairpin fold- Yuri L Lyubchenko, University of Nebraska Medical Center | Abstract

Advances in Antibiotics & Antibodies

Abstract

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Antibodies & Protein Engineering 2017: Nano-assembly of amyloid β peptide: Role of the hairpin fold- Yuri L Lyubchenko, University of Nebraska Medical Center

Author(s): Yuri L Lyubchenko

Increasing evidence suggests that the self-assembly of amyloid β(Aβ) protein underlies the early onset of Alzheimer’s disease (AD). Given that small Aβ nano-assemblies (oligomers) are the most neurotoxic species, they have become the major target for the development of treatments and early diagnostic tools for AD. However, advances surrounding this are blocked by the lack of structure intrinsic to Aβ oligomers, as they are transient states of Aβ aggregation kinetics; making traditional structural approaches non-amenable. We have previously developed single-molecule approaches capable of probing of aµΨλoιδπειδεσ dimers. Here, we extended our approaches to higher order oligomers. We hypothesized that the folding pattern of amyloid protein defines the aggregation pathway.

Methodology & Theoretical Orientation: In this study, we tested this hypothesis using Aβ(14-23) peptide in linear form and its tandem assembled in the hairpin-type shape. We combined two experimental approaches and molecular dynamics simulations to characterize molecular interactions and the stability of complexes between Aβ(14-23) hairpin and Aβ(14-23) monomer, as well as the interactions between two hairpins.

 

Findings: The lifetime measurements demonstrate that the Aβ(14-23) hairpin and a Aβ(14-23) monomer assemble in a very stable complex when compared with homologous ensembles. We measured the strength of hairpin-hairpin and hairpin-monomer interactions which demonstrated that the hairpin-monomer interaction is stronger compared with the hairpin-hairpin assembly; data that is fully in line with the lifetime measurements. Aggregation studies demonstrate that the Aβ(14-23) monomer formed fibrils and the hairpin formed spherical structures. However, their mixture formed neither fibrils nor spherical structures, but rather diskshaped nanostructures.

Conclusion & Significance: Overall, our study provides new insight into the role of the monomer structure on the self-assembly process that contributes to the formation of disease aggregates. Importantly, the developed experimental approaches and validation approaches for computational analyses are not limited to amyloid proteins, but can also be applied to other molecular systems.

Auxiliary examinations have uncovered that β clip structures are normal highlights in amyloid fibrils, proposing that these themes assume a significant job in amyloid get together. To test this speculation, we described the impact of the clip overlay on the accumulation procedure utilizing a model β fastener structure, comprising of two Aβ(14–23) monomers associated by a turn framing YNGK peptide. AFM investigations of the gathered totals uncovered that the clasp structures circular structures while direct Aβ(14–23) monomers structure fibrils. Also, an equimolar blend of the monomer and the clip collects into non-fibrillar totals, exhibiting that the barrette overlay significantly changes the morphology of gathered amyloid totals. To comprehend the atomic component basic the job of the barrette overlap on amyloid get together, we performed single-particle examining analyses to gauge cooperations among fastener and monomer and two clip edifices. The examinations uncover that the security of barrette monomer edifices is a lot higher than clasp fastener buildings. Sub-atomic elements reenactments uncovered a novel intercalated complex for the clip and monomer and Monte Carlo displaying additionally exhibited that such nano-congregations have raised steadiness contrasted and security of the dimer framed by Aβ(14–23) barrette. The job of such collapsing on the amyloid get together is likewise talked about.

The self-gathering of amyloid proteins into nano-totals is as of now considered the primary sub-atomic instrument prompting the improvement of beginning stage Alzheimer's malady and other amyloid-type neurodegenerative diseases1,2,3. The conglomeration procedure is joined by an adjustment in the optional structure of the monomers, in the long run prompting the get together of the fibrillar structures found in amyloid plaques4,5,6. Strong state NMR investigations of amyloid fibrils uncovered that cross β structures with either an equal or an antiparallel plan of monomers are the basic highlights of fibrils7, 8. Another element of fibrils is the nearness of 'β clasp' motifs9, 10, for example, the divert like structure from deposits 26 to 30 in Aβ42 fibrils11. As of late, Maiti et al. have distinguished β clasp structures in Aβ40 oligomers utilizing surface improved Raman spectroscopy and strong state NMR studies12. Essentially, a turn like compliance has been found in Aβ42 oligomers inside buildups 25–2913. As of late, the structure of a β-clip conformer of an Aβ40 monomer was balanced out by a neutralizer, recommending that the clasp structure could be a middle of the road during Aβ aggregation14. It has likewise been recommended that the turn compliance in Aβ is an early collapsing occasion during Aβ fibril nucleation15, 16. Together, these discoveries recommend that the β-clip structure is a typical theme in amyloid totals, anyway the job of the barrette adaptation in the gathering of oligomers and totals stay tricky. Among totals, the oligomeric as opposed to fibrillar structures are considered as the more neurotoxic species13. Subsequently, considering the structure of these totals and clarifying the component of how oneself get together procedure happens is vital for the improvement of suitable helpful and demonstrative instruments for amyloid ailments.

Ongoing examinations have exhibited that solitary atom approaches are a compelling strategy to consider oligomers17,18,19,20. Already, we built up an AFM power spectroscopy approach that permitted us to test the get together of amyloid proteins and peptides in dimers21,22,23; a significant finding of which being that amyloid dimers are profoundly steady. These discoveries were additionally upheld by straightforwardly estimating the lifetime of dimers by utilizing a solitary atom fluorescence approach named the fastened methodology for examining of intermolecular associations (TAPIN)24, 25. Computational demonstrating approaches, for example, sub-atomic elements (MD) reenactments were likewise utilized during auxiliary investigations of amyloid oligomers26, 27. We applied MD recreation to describe Aβ(14–23) amassed into dimers and built up a computational methodology dependent on the Monte Carlo reproductions empowering us to portray the structure of Aβ(14–23) dimers tested by the AFM pulling experiments28.

In the current investigation, we address the subject of how the barrette type auxiliary structure of amyloid β adds to the amyloid get together procedure. A β clip amyloid structure was developed by interfacing two Aβ(14–23) monomers with a turn framing YNGK tetra peptide. The test examines uncover that the fastener overlap assumes an emotional job in oneself gathering procedure of Aβ(14–23) peptides. The Aβ(14–23) clasp shaped progressively stable edifices contrasted with those framed by Aβ(14–23) monomers. Computational displaying of the Aβ(14–23) fastener and monomer edifices uncovers a sandwich type structure in which the monomer intercalates into the clasp, which is joined by an expanded dependability. The job of such momentarily shaped barrette overlap on the total procedure of amyloid proteins is talked about.

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