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      Long-range Regulation of Partially Folded Amyloidogenic Peptides

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          Abstract

          Neurodegeneration involves abnormal aggregation of intrinsically disordered amyloidogenic peptides (IDPs), usually mediated by hydrophobic protein-protein interactions. There is mounting evidence that formation of α-helical intermediates is an early event during self-assembly of amyloid-β42 (Aβ42) and α-synuclein (αS) IDPs in Alzheimer’s and Parkinson’s disease pathogenesis, respectively. However, the driving force behind on-pathway molecular assembly of partially folded helical monomers into helical oligomers assembly remains unknown. Here, we employ extensive molecular dynamics simulations to sample the helical conformational sub-spaces of monomeric peptides of both Aβ42 and αS. Our computed free energies, population shifts, and dynamic cross-correlation network analyses reveal a common feature of long-range intra-peptide modulation of partial helical folds of the amyloidogenic central hydrophobic domains via concerted coupling with their charged terminal tails (N-terminus of Aβ42 and C-terminus of αS). The absence of such inter-domain fluctuations in both fully helical and completely unfolded (disordered) states suggests that long-range coupling regulates the dynamicity of partially folded helices, in both Aβ42 and αS peptides. The inter-domain coupling suggests a form of intra-molecular allosteric regulation of the aggregation trigger in partially folded helical monomers. This approach could be applied to study the broad range of amyloidogenic peptides, which could provide a new path to curbing pathogenic aggregation of partially folded conformers into oligomers, by inhibition of sites far from the hydrophobic core.

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          Most cited references 70

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          Experimental constraints on quaternary structure in Alzheimer's beta-amyloid fibrils.

          We describe solid-state nuclear magnetic resonance (NMR) measurements on fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)) that place constraints on the identity and symmetry of contacts between in-register, parallel beta-sheets in the fibrils. We refer to these contacts as internal and external quaternary contacts, depending on whether they are within a single molecular layer or between molecular layers. The data include (1) two-dimensional 13C-13C NMR spectra that indicate internal quaternary contacts between side chains of L17 and F19 and side chains of I32, L34, and V36, as well as external quaternary contacts between side chains of I31 and G37; (2) two-dimensional 15N-13C NMR spectra that indicate external quaternary contacts between the side chain of M35 and the peptide backbone at G33; (3) measurements of magnetic dipole-dipole couplings between the side chain carboxylate group of D23 and the side chain amine group of K28 that indicate salt bridge interactions. Isotopic dilution experiments allow us to make distinctions between intramolecular and intermolecular contacts. On the basis of these data and previously determined structural constraints from solid-state NMR and electron microscopy, we construct full molecular models using restrained molecular dynamics simulations and restrained energy minimization. These models apply to Abeta(1-40) fibrils grown with gentle agitation. We also present evidence for different internal quaternary contacts in Abeta(1-40) fibrils grown without agitation, which are morphologically distinct.
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            Evidence for a partially folded intermediate in alpha-synuclein fibril formation.

            Intracellular proteinaceous aggregates (Lewy bodies and Lewy neurites) of alpha-synuclein are hallmarks of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple systemic atrophy. However, the molecular mechanisms underlying alpha-synuclein aggregation into such filamentous inclusions remain unknown. An intriguing aspect of this problem is that alpha-synuclein is a natively unfolded protein, with little or no ordered structure under physiological conditions. This raises the question of how an essentially disordered protein is transformed into highly organized fibrils. In the search for an answer to this question, we have investigated the effects of pH and temperature on the structural properties and fibrillation kinetics of human recombinant alpha-synuclein. Either a decrease in pH or an increase in temperature transformed alpha-synuclein into a partially folded conformation. The presence of this intermediate is strongly correlated with the enhanced formation of alpha-synuclein fibrils. We propose a model for the fibrillation of alpha-synuclein in which the first step is the conformational transformation of the natively unfolded protein into the aggregation-competent partially folded intermediate.
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              Structure and dynamics of micelle-bound human alpha-synuclein.

              Misfolding of the protein alpha-synuclein (aS), which associates with presynaptic vesicles, has been implicated in the molecular chain of events leading to Parkinson's disease. Here, the structure and dynamics of micelle-bound aS are reported. Val3-Val37 and Lys45-Thr92 form curved alpha-helices, connected by a well ordered, extended linker in an unexpected anti-parallel arrangement, followed by another short extended region (Gly93-Lys97), overlapping the recently identified chaperone-mediated autophagy recognition motif and a highly mobile tail (Asp98-Ala140). Helix curvature is significantly less than predicted based on the native micelle shape, indicating a deformation of the micelle by aS. Structural and dynamic parameters show a reduced helical content for Ala30-Val37. A dynamic variation in interhelical distance on the microsecond timescale is complemented by enhanced sub-nanosecond timescale dynamics, particularly in the remarkably glycine-rich segments of the helices. These unusually rich dynamics may serve to mitigate the effect of aS binding on membrane fluidity. The well ordered conformation of the helix-helix connector indicates a defined interaction with lipidic surfaces, suggesting that, when bound to larger diameter synaptic vesicles, it can act as a switch between this structure and a previously proposed uninterrupted helix.
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                Author and article information

                Contributors
                damien.thompson@ul.ie
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                5 May 2020
                5 May 2020
                2020
                : 10
                Affiliations
                ISNI 0000 0004 1936 9692, GRID grid.10049.3c, Department of Physics, , Bernal Institute, University of Limerick, ; Limerick, V94 T9PX Ireland
                Article
                64303
                10.1038/s41598-020-64303-x
                7200734
                32371882
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001602, Science Foundation Ireland (SFI);
                Award ID: 15/CDA/3491
                Award ID: 15/CDA/3491
                Award ID: 15/CDA/3491
                Award Recipient :
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                © The Author(s) 2020

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                molecular dynamics, computational models, computational chemistry

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