Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Aggregation Condition-Structure Relationship of Mouse Prion Protein Fibrils.

ABSTRACT: Prion diseases are associated with conformational conversion of cellular prion protein into a misfolded pathogenic form, which resembles many properties of amyloid fibrils. The same prion protein sequence can misfold into different conformations, which are responsible for variations in prion disease phenotypes (prion strains). In this work, we use atomic force microscopy, FTIR spectroscopy and magic-angle spinning NMR to devise structural models of mouse prion protein fibrils prepared in three different denaturing conditions. We find that the fibril core region as well as the structure of its N- and C-terminal parts is almost identical between the three fibrils. In contrast, the central part differs in length of β-strands and the arrangement of charged residues. We propose that the denaturant ionic strength plays a major role in determining the structure of fibrils obtained in a particular condition by stabilizing fibril core interior-facing glutamic acid residues.

SUBMITTER: Fridmanis J

PROVIDER: S-EPMC8431800 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Elongation of mouse prion protein amyloid-like fibrils: effect of temperature and denaturant concentration.

Project description:Prion protein is known to have the ability to adopt a pathogenic conformation, which seems to be the basis for protein-only infectivity. The infectivity is based on self-replication of this pathogenic prion structure. One of possible mechanisms for such replication is the elongation of amyloid-like fibrils. We measured elongation kinetics and thermodynamics of mouse prion amyloid-like fibrils at different guanidine hydrochloride (GuHCl) concentrations. Our data show that both increases in temperature and GuHCl concentration help unfold monomeric protein and thus accelerate elongation. Once the monomers are unfolded, further increases in temperature raise the rate of elongation, whereas the addition of GuHCl decreases it. We demonstrated a possible way to determine different activation energies of amyloid-like fibril elongation by using folded and unfolded protein molecules. This approach separates thermodynamic data for fibril-assisted monomer unfolding and for refolding and formation of amyloid-like structure.

| S-EPMC3991587 | biostudies-literature

Formation and properties of amyloid fibrils of prion protein.

Project description:Amyloid fibrils formed from prion protein (PrP) are associated with prion diseases. In this review we discuss a number of extrinsic and intrinsic experimental factors related to the formation of PrP amyloid fibrils in vitro. We first examined the effects of ultrasonic power on the induction of amyloid fibrillation from PrP. The most important conclusion drawn from the results is that an applied ultrasonic power of approximately 2 W enhanced the nucleation of amyloid fibrils efficiently but that more powerful ultrasonication led to retardation of growth. We also reviewed evidence on the amyloidogenic regions of PrP based on peptide screening throughout the polypeptide sequence. These results showed that helix 2 (H2) peptides of PrP were capable of both the fibrillation and propagation of straight, long fibrils. Moreover, the conformation of preformed H2 fibrils changed reversibly depending on the pH of the solution, implying that interactions between side-chains modulated the conformation of amyloid fibrils. The evidence discussed in this review relates specifically to PrP but may be relevant to other amyloidogenic proteins.

| S-EPMC5899736 | biostudies-literature

Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils.

Project description: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.

| S-EPMC8151363 | biostudies-literature

2.7 A cryo-EM structure of ex vivo RML prion fibrils.

Project description:Mammalian prions propagate as distinct strains and are composed of multichain assemblies of misfolded host-encoded prion protein (PrP). Here, we present a near-atomic resolution cryo-EM structure of PrP fibrils present in highly infectious prion rod preparations isolated from the brains of RML prion-infected mice. We found that prion rods comprise single-protofilament helical amyloid fibrils that coexist with twisted pairs of the same protofilaments. Each rung of the protofilament is formed by a single PrP monomer with the ordered core comprising PrP residues 94-225, which folds to create two asymmetric lobes with the N-linked glycans and the glycosylphosphatidylinositol anchor projecting from the C-terminal lobe. The overall architecture is comparable to that of recently reported PrP fibrils isolated from the brain of hamsters infected with the 263K prion strain. However, there are marked conformational variations that could result from differences in PrP sequence and/or represent distinguishing features of the distinct prion strains.

| S-EPMC9279362 | biostudies-literature

Infectious mouse-adapted RML scrapie prion fibrils purified from terminally-infected mouse brains

Project description: Not available

| EMPIAR-10992 | biostudies-other

Interaction between prion protein and A? amyloid fibrils revisited.

Project description:Recent studies indicate that the pathogenesis of Alzheimer disease may be related to the interaction between prion protein (PrP) and certain oligomeric species of A? peptide. However, the mechanism of this interaction remains unclear and controversial. Here we provide direct experimental evidence that, in addition to previously demonstrated binding to A? oligomers, PrP also interacts with mature A? fibrils. However, contrary to the recent claim that PrP causes fragmentation of A? fibrils into oligomeric species, no evidence for such a disassembly could be detected in the present study. In contrast, our data indicate that the addition of PrP to preformed A? fibrils results in a lateral association of individual fibrils into larger bundles. These findings have potentially important implications for understanding the mechanism by which PrP might impact A? toxicity as well as for the emerging efforts to use PrP-derived compounds as inhibitors of A?-induced neurodegeneration.

| S-EPMC4030797 | biostudies-other

Formation of distinct prion protein amyloid fibrils under identical experimental conditions.

Project description:Protein aggregation into amyloid fibrils is linked to multiple neurodegenerative disorders, such as Alzheimer's, Parkinson's or Creutzfeldt-Jakob disease. A better understanding of the way these aggregates form is vital for the development of drugs. A large detriment to amyloid research is the ability of amyloidogenic proteins to spontaneously aggregate into multiple structurally distinct fibrils (strains) with different stability and seeding properties. In this work we show that prion proteins are capable of forming more than one type of fibril under the exact same conditions by assessing their Thioflavin T (ThT) binding ability, morphology, secondary structure, stability and seeding potential.

| S-EPMC7067779 | biostudies-literature

Dissecting structure of prion amyloid fibrils by hydrogen-deuterium exchange ultraviolet Raman spectroscopy.

Project description:The molecular mechanisms underlying structural diversity of amyloid fibrils or prion strains formed within the same primary structure is considered to be one of the most enigmatic questions in prion biology. We report here on the direct characterization of amyloid structures using a novel spectroscopic technique, hydrogen-deuterium exchange ultraviolet Raman spectroscopy. This method enables us to assess the structural differences within highly ordered cross-?-cores of two amyloid states produced within the same amino acid sequence of full-length mammalian prion protein. We found that while both amyloid states consisted of ?-structures, their cross-?-cores exhibited hydrogen bonding of different strengths. Moreover, Raman spectroscopy revealed that both amyloid states displayed equally narrow crystalline-like bands, suggesting uniform structures of cross-?-cores within each state. Taken together, these data suggest that highly polymorphous fibrils can display highly uniform structures of their cross-?-core and belong to the same prion strain.

| S-EPMC3490051 | biostudies-literature

ER stress causes widespread protein aggregation and prion formation.

Project description:Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.

| S-EPMC5551711 | biostudies-literature

Ex vivo mammalian prions are formed of paired double helical prion protein fibrils.

Project description:Mammalian prions are hypothesized to be fibrillar or amyloid forms of prion protein (PrP), but structures observed to date have not been definitively correlated with infectivity and the three-dimensional structure of infectious prions has remained obscure. Recently, we developed novel methods to obtain exceptionally pure preparations of prions from mouse brain and showed that pathogenic PrP in these high-titre preparations is assembled into rod-like assemblies. Here, we have used precise cell culture-based prion infectivity assays to define the physical relationship between the PrP rods and prion infectivity and have used electron tomography to define their architecture. We show that infectious PrP rods isolated from multiple prion strains have a common hierarchical assembly comprising twisted pairs of short fibres with repeating substructure. The architecture of the PrP rods provides a new structural basis for understanding prion infectivity and can explain the inability to systematically generate high-titre synthetic prions from recombinant PrP.

| S-EPMC4892434 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data