Conserved amyloid core structure of stop mutants of the human prion protein

Zweckstetter, Markus

doi:10.4161/pri.23956

Cited by 11 publications

(11 citation statements)

References 27 publications

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“…PrP(120 -144) forms S-shaped, U-shaped, and ⍀-shaped protofilament structures via multiple nucleation-dependent pathways. The PrP(120 -144) protofilaments mainly contain parallel in-register ␤-sheets, which are consistent with previous experimental work (20,23). The key event during the aggregation is the formation of a nucleus consisting of a parallel in-register ␤-sheet dimer.…”

Section: Postulated a Trimeric Model For Prpsupporting

confidence: 90%

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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Section: Postulated a Trimeric Model For Prpsupporting

confidence: 90%

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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“…First, we created a PrP construct 23–144 with a stop codon mutation at residue 145 [PrP (Y145Stop)] resulting in a truncated protein that adopts a completely disordered state as evident by its CD signature (Figure S8A). We would also like to note here that this mutation has a pathological significance, giving rise to the GSS-phenotype . If the SERS enhancement in PrP indeed arises from an intrinsically disordered region, we should observe similar SERS spectra of PrP-Y145Stop to that of the full-length PrP (23–231) with some minor differences due to a weaker enhancement of the C-terminal globular domain of the full-length protein.…”

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confidence: 64%

Ultrasensitive Characterization of the Prion Protein by Surface-Enhanced Raman Scattering: Selective Enhancement via Electrostatic Tethering of the Intrinsically Disordered Domain with Functionalized Silver Nanoparticles

Singh

Agarwal

Avni

et al. 2021

J. Phys. Chem. Lett.

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Surface-enhanced Raman scattering (SERS) circumvents the inherent insensitivity of Raman spectroscopy and offers a powerful tool for the ultrasensitive detection and characterization of biomolecules at low concentrations. Here we show that SERS via electrostatic tethering between surface-modified negatively charged silver nanoparticles and highly positively charged intrinsically disordered N-terminal domain of the prion protein allows highly sensitive and reproducible protein detection and characterization at as low as hundreds of nanomolar protein concentrations. These measurements preferentially illuminate a selective part of the protein due to a sharp dependence of the near-field intensity on the distance between the nanoparticle surface and the protein. We also demonstrate that by shortening the length of the disordered tail it is possible to achieve a domain-selective Raman enhancement to study the C-terminal globular domain. Our tether-length-dependent SERS methodology will serve as a potent, noninvasive, and label-free strategy to detect and characterize a wide range of proteins possessing disordered segments.

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“…Solid-state NMR spectroscopy has now reached a level at which it can reliably determine the 3-D structure of single molecules in amyloid fibrils [ 22 – 25 ]. In combination with information from other techniques, such as electron microscopy and modeling, this approach can also provide insights into the higher order arrangements of molecules in prion aggregates [ 26 , 27 ].…”

Section: Five Approachesmentioning

confidence: 99%

Elucidating the structure of an infectious protein

Zweckstetter¹,

Requena²,

Wille³

2017

PLoS Pathog

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Conserved amyloid core structure of stop mutants of the human prion protein

Abstract: To cite this article: Markus Zweckstetter (2013) Conserved amyloid core structure of stop mutants of the human prion protein, Prion, 7:3,[193][194][195][196][197]

Cited by 11 publications

References 27 publications

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

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

Ultrasensitive Characterization of the Prion Protein by Surface-Enhanced Raman Scattering: Selective Enhancement via Electrostatic Tethering of the Intrinsically Disordered Domain with Functionalized Silver Nanoparticles

Elucidating the structure of an infectious protein

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