Codon 129 polymorphism of the human prion protein influences the kinetics of amyloid formation

The human prion protein (PrP) has a common polymorphism at residue 129, which can be valine or methionine. This polymorphism has a strong influence on susceptibility to prion diseases and on prion-strain properties. Previous work has shown that this amino acid variation has no measurable effect on the native structure of cellular PrP (PrPC). Here, it is shown that the polymorphism does not change the efficiency of conversion to the β-PrP conformation or affect the binding of copper(II) ions. However, in a partially denatured conformation, the polymorphic variation has a profound influence on the ability of the protein to form amyloid fibrils spontaneously.

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Cryo-EM structure of disease-related prion fibrils provides insights into seeding barriers

10.1101/2021.08.10.455830 ◽

2021 ◽

Author(s):

Qiuye Li ◽

Christopher P. Jaroniec ◽

Witold K. Surewicz

Keyword(s):

High Resolution ◽

Prion Protein ◽

Prion Disease ◽

Amyloid Fibrils ◽

Prion Diseases ◽

Protein Aggregates ◽

Direct Support ◽

Human Prion Protein ◽

Structural Insight

One of the least understood aspects of prion diseases is the structure of infectious prion protein aggregates. Here we report a high-resolution cryo-EM structure of amyloid fibrils formed by human prion protein with Y145Stop mutation that is associated with a familial prion disease. This structural insight allows us not only to explain previous biochemical findings, but also provides direct support for the conformational adaptability model of prion transmissibility barriers.

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Distinct Stability States of Disease-Associated Human Prion Protein Identified by Conformation-Dependent Immunoassay

Journal of Virology ◽

10.1128/jvi.01057-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 12030-12038 ◽

Cited By ~ 23

Author(s):

Young Pyo Choi ◽

Alexander H. Peden ◽

Albrecht Gröner ◽

James W. Ironside ◽

Mark W. Head

Keyword(s):

Prion Protein ◽

Fragment Size ◽

Prion Diseases ◽

Conformational Stability ◽

Site Occupancy ◽

Glycosylation Site ◽

Jakob Disease ◽

Human Prion Protein ◽

Conformation Stability ◽

Codon 129

ABSTRACT The phenotypic and strain-related properties of human prion diseases are, according to the prion hypothesis, proposed to reside in the physicochemical properties of the conformationally altered, disease-associated isoform of the prion protein (PrPSc), which accumulates in the brains of patients suffering from Creutzfeldt-Jakob disease and related conditions, such as Gerstmann-Straussler-Scheinker disease. Molecular strain typing of human prion diseases has focused extensively on differences in the fragment size and glycosylation site occupancy of the protease-resistant prion protein (PrPres) in conjunction with the presence of mutations and polymorphisms in the prion protein gene (PRNP). Here we report the results of employing an alternative strategy that specifically addresses the conformational stability of PrPSc and that has been used previously to characterize animal prion strains transmitted to rodents. The results show that there are at least two distinct conformation stability states in human prion diseases, neither of which appears to correlate fully with the PrPres type, as judged by fragment size or glycosylation, the PRNP codon 129 status, or the presence or absence of mutations in PRNP. These results suggest that conformational stability represents a further dimension to a complete description of potentially phenotype-related properties of PrPSc in human prion diseases.

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Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils

International Journal of Molecular Sciences ◽

10.3390/ijms22105075 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5075

Author(s):

Mantas Ziaunys ◽

Andrius Sakalauskas ◽

Kamile Mikalauskaite ◽

Ruta Snieckute ◽

Vytautas Smirnovas

Keyword(s):

Protein Aggregation ◽

Prion Protein ◽

Amyloid Fibrils ◽

Prion Diseases ◽

Morphological Properties ◽

Large Sample Size ◽

Structural Variations ◽

Temperature Dependent ◽

Protein Fibrils ◽

Propagation Properties

Prion protein aggregation into amyloid fibrils is associated with the onset and progression of prion diseases—a group of neurodegenerative amyloidoses. The process of such aggregate formation is still not fully understood, especially regarding their polymorphism, an event where the same type of protein forms multiple, conformationally and morphologically distinct structures. Considering that such structural variations can greatly complicate the search for potential antiamyloid compounds, either by having specific propagation properties or stability, it is important to better understand this aggregation event. We have recently reported the ability of prion protein fibrils to obtain at least two distinct conformations under identical conditions, which raised the question if this occurrence is tied to only certain environmental conditions. In this work, we examined a large sample size of prion protein aggregation reactions under a range of temperatures and analyzed the resulting fibril dye-binding, secondary structure and morphological properties. We show that all temperature conditions lead to the formation of more than one fibril type and that this variability may depend on the state of the initial prion protein molecules.

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Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

Biomolecular NMR Assignments ◽

10.1007/s12104-021-10005-y ◽

2021 ◽

Vol 15 (1) ◽

pp. 193-196

Author(s):

Máximo Sanz-Hernández ◽

Alfonso De Simone

Keyword(s):

Prion Protein ◽

Nmr Assignments ◽

Chemical Shifts ◽

Prion Diseases ◽

Random Coil ◽

Transmissible Spongiform Encephalopathies ◽

Globular Domain ◽

Structural Elements ◽

Spongiform Encephalopathies ◽

Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

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Inter-Oligomer Interactions of the Human Prion Protein Are Modulated by the Polymorphism at Codon 129

Journal of Molecular Biology ◽

10.1016/j.jmb.2008.05.057 ◽

2008 ◽

Vol 381 (1) ◽

pp. 212-220 ◽

Cited By ~ 15

Author(s):

Remo Gerber ◽

Kislon Voitchovsky ◽

Clement Mitchel ◽

Abdessamad Tahiri-Alaoui ◽

John F. Ryan ◽

...

Keyword(s):

Prion Protein ◽

Human Prion Protein ◽

Codon 129

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Structural effects of the highly protective V127 polymorphism on human prion protein

Communications Biology ◽

10.1038/s42003-020-01126-6 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Laszlo L. P. Hosszu ◽

Rebecca Conners ◽

Daljit Sangar ◽

Mark Batchelor ◽

Elizabeth B. Sawyer ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Structural Changes ◽

Prion Diseases ◽

Single Point ◽

Structural Basis ◽

Single Point Mutation ◽

Solution Dynamics ◽

Human Prion Protein ◽

Prion Transmission

AbstractPrion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP β-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the β2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease.

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Sulphated glycosaminoglycans prevent the neurotoxicity of a human prion protein fragment

Biochemical Journal ◽

10.1042/bj3350369 ◽

1998 ◽

Vol 335 (2) ◽

pp. 369-374 ◽

Cited By ~ 44

Author(s):

Mar PÉREZ ◽

Francisco WANDOSELL ◽

Camilo COLAÇO ◽

Jesús AVILA

Keyword(s):

Prion Protein ◽

Amyloid Fibrils ◽

Transmissible Spongiform Encephalopathies ◽

Therapeutic Effects ◽

Protein Fragment ◽

Spongiform Encephalopathies ◽

Sulphated Polysaccharides ◽

Human Prion Protein ◽

Sulphated Glycosaminoglycans

Although a number of features distinguish the disease isoform of the prion protein (PrPSc) from its normal cellular counterpart (PrPC) in the transmissible spongiform encephalopathies (TSEs), the neuropathogenesis of these diseases remains an enigma. The amyloid fibrils formed by fragments of human PrP have, however, been shown to be directly neurotoxic in vitro. We show here that sulphated polysaccharides (heparin, keratan and chondroitin) inhibit the neurotoxicity of these amyloid fibrils and this appears to be mediated via inhibition of the polymerization of the PrP peptide into fibrils. This provides a rationale for the therapeutic effects of sulphated polysaccharides and suggests a rapid in vitro functional screen for TSE therapeutics.

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