Determination of amyloid core structure using chemical shifts

Skora, Lukasz; Zweckstetter, Markus

doi:10.1002/pro.2170

Cited by 11 publications

(16 citation statements)

References 45 publications

(44 reference statements)

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“…Met-129 shows a pronounced reduction of solvent accessibility in the amyloid state (Fig. 4), in line with the structural model proposed for the Y145X stop mutant (48).…”

Section: Discussionsupporting

confidence: 88%

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Burial of the Polymorphic Residue 129 in Amyloid Fibrils of Prion Stop Mutants

Skora

Fonseca‐Ornelas

Hofele

et al. 2013

Journal of Biological Chemistry

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“…Met-129 shows a pronounced reduction of solvent accessibility in the amyloid state (Fig. 4), in line with the structural model proposed for the Y145X stop mutant (48).…”

Section: Discussionsupporting

confidence: 88%

“…Recently, some of us determined the backbone fold of amyloid fibrils of the Y145X stop mutant by application of the CSRosetta structure calculation program to experimental solidstate NMR chemical shifts (24,48). The calculations revealed a left-handed ␤-helix formed by three ␤-strands.…”

Section: Discussionmentioning

confidence: 99%

Burial of the Polymorphic Residue 129 in Amyloid Fibrils of Prion Stop Mutants

Skora

Fonseca‐Ornelas

Hofele

et al. 2013

Journal of Biological Chemistry

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“…Later on, based on solid-state NMR data, Lin et al (21) presented a parallel in-register ␤-sheet model for the human PrP(127-147) fibril where each peptide has two straight ␤-strands connected by a kink at Pro-137. Skora and Zweckstetter (22) applied the chemical shift ROSETTA method and predicted the conformation of human PrP(112-141) within the amyloid core formed by the Y145Stop prion mutant. Later on, Zweckstetter (23) used a combination of NMR spectroscopy, hydroxyl radical probing combined with mass spectrometry, electron microscopy, and computational methods to propose dimeric and trimeric left-handed ␤-helix models for the PrP(112-141) amyloid core.…”

Section: Postulated a Trimeric Model For Prpmentioning

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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“…7,8 The amyloid core of both mutants is formed by a small, hydrogen-bonded region comprising residues 109-142. 7,9 Residues 144-156, which form helix1 in the native structure of humPrP, 10 are not part of this core, in agreement with antibody staining.…”

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confidence: 99%

“…1A-C). 7,8 The β-helix comprises three β-strands. (www.nrc.bu.edu/cluster) were ranked according to electrostatic, hydrophobic and van der Waals interactions.…”

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confidence: 99%