Conformational Plasticity of the Gerstmann–Sträussler–Scheinker Disease Peptide as Indicated by Its Multiple Aggregation Pathways

Natalello, Antonino; Prokorov, Valery V.; Tagliavini, Fabrizio; Morbin, Michela; Forloni, Gianluigi; Beeg, Marten; Manzoni, Claudia; Colombo, Laura; Gobbi, Marco; Salmona, Mario; Doglia, Silvia Maria

doi:10.1016/j.jmb.2008.06.063

Cited by 55 publications

(58 citation statements)

References 62 publications

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“…Moreover, the antiparallel b-sheet organization of Ab(1-40) oligomers has been previously suggested in Habicht et al [19] and is in agreement with previous structural studies carried out on Ab(1-42) oligomers [20,21] as well as on other proteins forming oligomers like b 2 -microglobulin [53] and PrP (prion related protein) peptide [PrP-(82-146)] [54]. Additionally, Ab oligomers are recognized by the A11 antibody.…”

Section: Discussionsupporting

confidence: 89%

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Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

135

119

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Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Ab) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Ab(1-40), starting from monomeric Ab to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel b-sheet. These structural changes are described in terms of H-bonding rupture/formation, b-strands reorientation and b-sheet elongation. As antiparallel b-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the b-sheet implicating a reorientation of b-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates.

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Section: Discussionsupporting

confidence: 89%

“…As antiparallel b-sheet structure is also observed for other proteins forming oligomers [53,54], the reorganization of b-sheet implicating a reorientation of b-strands could be a generic mechanism determining the kinetics and controlling the protein misfolding to form inert fibrils.…”

Section: Discussionmentioning

confidence: 87%

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

135

119

View full text Add to dashboard Cite

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“…Several studies have found multiple aggregation pathways for amyloidogenic proteins. Natalello et al (40) used a combination of Fourier transform infrared spectroscopy and atomic force microscopy to find that human Pr(82-146) undergoes multiple aggregation pathways to form fibrils with various types of secondary structure. Also, Cheon et al (26) found in DMD/PRIME20 simulations that A␤ assembles from an oligomer state to a U-shaped protofilament via two distinct pathways.…”

Section: Discussionmentioning

confidence: 99%

N-terminal Prion Protein Peptides (PrP(120–144)) Form Parallel In-register β-Sheets via Multiple Nucleation-dependent Pathways

Wang

Shao

Hall

2016

Journal of Biological Chemistry

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The prion diseases are a family of fatal neurodegenerative diseases associated with the misfolding and accumulation of normal prion protein (PrP C ) into its pathogenic scrapie form (PrP Sc ). Understanding the fundamentals of prion protein aggregation and the molecular architecture of PrP Sc is key to unraveling the pathology of prion diseases. Our work investigates the early-stage aggregation of three prion protein peptides, corresponding to residues 120 -144 of human (Hu), bank vole (BV), and Syrian hamster (SHa) prion protein, from disordered monomers to ␤-sheet-rich fibrillar structures. Using 12 s discontinuous molecular dynamics simulations combined with the PRIME20 force field, we find that the Hu-, BV-, and SHaPrP(120 -144) aggregate via multiple nucleation-dependent pathways to form U-shaped, S-shaped, and ⍀-shaped protofilaments. The S-shaped HuPrP(120 -144) protofilament is similar to the amyloid core structure of HuPrP(112-141) predicted by Zweckstetter. HuPrP(120 -144) has a shorter aggregation lag phase than BVPrP(120 -144) followed by SHaPrP(120 -144), consistent with experimental findings. Two amino acid substitutions I138M and I139M retard the formation of parallel in-register ␤-sheet dimers during the nucleation stage by increasing side chain-side chain association and reducing side chain interaction specificity. On average, HuPrP(120 -144) aggregates contain more parallel ␤-sheet content than those formed by BV-and SHaPrP(120 -144). Deletion of the C-terminal residues 138 -144 prevents formation of fibrillar structures in agreement with the experiment. This work sheds light on the amyloid core structures underlying prion strains and how I138M, I139M, and S143N affect prion protein aggregation kinetics.Prion diseases are a family of infectious amyloid diseases that affect both humans and animals. They include Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, kuru, and fatal familial insomnia in humans, and scrapie, bovine spongiform encephalopathy, and chronic wasting disease in other mammals (1). The infectious agent is the scrapie form of the prion protein (PrP Sc ), 2 which is a ␤-sheet-rich aggregated form of normal prion protein (PrP C ) whose full structure is unknown. In contrast to viruses or other pathogens, which propagate by replicating themselves inside a host cell based on their nucleic acid genome, PrP Sc propagates by templating the misfolding and accumulation of PrP C into misfolded PrP Sc (2). In addition, within a single population, e.g. human, various strains of Creutzfeldt-Jakob disease are believed to be caused by the same prion protein but with diverse PrP Sc conformations (3). The molecular mechanism underlying PrP Sc -assisted propagation still remains unclear (4).Various models for the full structure of PrP Sc have been postulated based on experiment and simulation studies. PrP Sc in which the N-terminal residues 89 -175 adopt a left-handed ␤-helix, and residues 176 -227 in the C terminus maintain an ␣-helical conformation. Using molecular dynamics si...

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“…S3). Interestingly, the detection of a difference in the organization of the β-sheet structure from a dominance of parallel β-sheet structure in the fibrillar form to that of antiparallel β-sheet structure in oligomeric species has been reported previously for αS (17) and for several other amyloidogenic peptides and proteins such as the Aβ-peptide (35), lysozyme (36), a prionrelated peptide (37), and β2-microglobulin (38).…”

Section: Definition Of the Secondary Structure Content And Hydrophobicmentioning

confidence: 59%

Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation

Chen

Drakulić

Deas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

429

661

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We describe the isolation and detailed structural characterization of stable toxic oligomers of α-synuclein that have accumulated during the process of amyloid formation. Our approach has allowed us to identify distinct subgroups of oligomers and to probe their molecular architectures by using cryo-electron microscopy (cryoEM) image reconstruction techniques. Although the oligomers exist in a range of sizes, with different extents and nature of β-sheet content and exposed hydrophobicity, they all possess a hollow cylindrical architecture with similarities to certain types of amyloid fibril, suggesting that the accumulation of at least some forms of amyloid oligomers is likely to be a consequence of very slow rates of rearrangement of their β-sheet structures. Our findings reveal the inherent multiplicity of the process of protein misfolding and the key role the β-sheet geometry acquired in the early stages of the self-assembly process plays in dictating the kinetic stability and the pathological nature of individual oligomeric species.protein misfolding | amyloid aggregation | toxic oligomer | cryoelectron microscopy | neurodegeneration

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Conformational Plasticity of the Gerstmann–Sträussler–Scheinker Disease Peptide as Indicated by Its Multiple Aggregation Pathways

Cited by 55 publications

References 62 publications

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

N-terminal Prion Protein Peptides (PrP(120–144)) Form Parallel In-register β-Sheets via Multiple Nucleation-dependent Pathways

Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation

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