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Acta Biochimica Et Biophysica Sinica Jun 2014The normal cellular prion protein, PrP(C) is a highly conserved and widely expressed cell surface glycoprotein in all mammals. The expression of PrP is pivotal in the... (Review)
Review
The normal cellular prion protein, PrP(C) is a highly conserved and widely expressed cell surface glycoprotein in all mammals. The expression of PrP is pivotal in the pathogenesis of prion diseases; however, the normal physiological functions of PrP(C) remain incompletely understood. Based on the studies in cell models, a plethora of functions have been attributed to PrP(C). In this paper, we reviewed the potential roles that PrP(C) plays in cell physiology and focused on its contribution to tumorigenesis.
Topics: Cell Adhesion; Cell Differentiation; Cell Movement; Cell Proliferation; Humans; Neoplasms; Prions
PubMed: 24681883
DOI: 10.1093/abbs/gmu019 -
Microbiology Spectrum Dec 2016Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi),... (Review)
Review
Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi), where they behave as cytoplasmic non-Mendelian genetic elements. Fungal prions correspond in most cases to fibrillary β-sheet-rich protein aggregates termed amyloids. Fungal prion models and, in particular, yeast prions were instrumental in the description of fundamental aspects of prion structure and propagation. These models established the "protein-only" nature of prions, the physical basis of strain variation, and the role of a variety of chaperones in prion propagation and amyloid aggregate handling. Yeast and fungal prions do not necessarily correspond to harmful entities but can have adaptive roles in these organisms.
Topics: Amyloid; Fungal Proteins; Fungi; Prions
PubMed: 28087950
DOI: 10.1128/microbiolspec.FUNK-0029-2016 -
Prion 2018Protein misfolding and aggregation into highly ordered fibrillar structures have been traditionally associated with pathological processes. Nevertheless, nature has... (Review)
Review
Protein misfolding and aggregation into highly ordered fibrillar structures have been traditionally associated with pathological processes. Nevertheless, nature has taken advantage of the particular properties of amyloids for functional purposes, like in the protection of organisms against environmental changing conditions. Over the last decades, these fibrillar structures have inspired the design of new nanomaterials with intriguing applications in biomedicine and nanotechnology such as tissue engineering, drug delivery, adhesive materials, biodegradable nanocomposites, nanowires or biosensors. Prion and prion-like proteins, which are considered a subclass of amyloids, are becoming ideal candidates for the design of new and tunable nanomaterials. In this review, we discuss the particular properties of this kind of proteins, and the current advances on the design of new materials based on prion sequences.
Topics: Amyloid; Animals; Biosensing Techniques; Drug Design; Humans; Nanomedicine; Nanostructures; Prions; Tissue Engineering
PubMed: 30196749
DOI: 10.1080/19336896.2018.1521235 -
Cold Spring Harbor Perspectives in... Sep 2016Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to... (Review)
Review
Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to lethal, with specific effects dependent on the prion protein and the specific prion variant ("prion strain"). The prion amyloids of Sup35p, Ure2p, and Rnq1p are in-register, parallel, folded β-sheets, an architecture that naturally suggests a mechanism by which a protein can template its conformation, just as DNA or RNA templates its sequence. Prion propagation is critically affected by an array of chaperone systems, most notably the Hsp104/Hsp70/Hsp40 combination, which is responsible for generating new prion seeds from old filaments. The Btn2/Cur1 antiprion system cures most [URE3] prions that develop, and the Ssb antiprion system blocks [PSI+] generation.
Topics: Amyloid; Fungal Proteins; Prions; Yeasts
PubMed: 27481532
DOI: 10.1101/cshperspect.a023531 -
Genetics Aug 2012The concept of a prion as an infectious self-propagating protein isoform was initially proposed to explain certain mammalian diseases. It is now clear that yeast also... (Review)
Review
The concept of a prion as an infectious self-propagating protein isoform was initially proposed to explain certain mammalian diseases. It is now clear that yeast also has heritable elements transmitted via protein. Indeed, the "protein only" model of prion transmission was first proven using a yeast prion. Typically, known prions are ordered cross-β aggregates (amyloids). Recently, there has been an explosion in the number of recognized prions in yeast. Yeast continues to lead the way in understanding cellular control of prion propagation, prion structure, mechanisms of de novo prion formation, specificity of prion transmission, and the biological roles of prions. This review summarizes what has been learned from yeast prions.
Topics: Prions; Yeasts
PubMed: 22879407
DOI: 10.1534/genetics.111.137760 -
Cold Spring Harbor Perspectives in... Feb 2017It is now established that numerous amyloid proteins associated with neurodegenerative diseases, including tau and α-synuclein, have essential characteristics of... (Review)
Review
It is now established that numerous amyloid proteins associated with neurodegenerative diseases, including tau and α-synuclein, have essential characteristics of prions, including the ability to create transmissible cellular pathology in vivo. We have developed cellular bioassays that report on the various features of prion activity using genetic engineering and quantitative fluorescence-based detection systems. We have exploited these biosensors to measure the binding and uptake of tau seeds into cells in culture and to quantify seeding activity in brain samples. These cell models have also been used to propagate tau prion strains indefinitely in culture. In this review, we illustrate the utility of cellular biosensors to gain mechanistic insight into prion transmission and to study neurodegenerative diseases in a reductionist fashion.
Topics: Animals; Biosensing Techniques; Brain; Cell Culture Techniques; Humans; Neurodegenerative Diseases; Prion Diseases; Prions; alpha-Synuclein; tau Proteins
PubMed: 27815306
DOI: 10.1101/cshperspect.a024026 -
PLoS Pathogens Jul 2019Prions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie...
Prions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie isoform (PrPSc) of the cellular prion protein (PrPC), caused epidemic and epizootic episodes [1]. Most aggregates of other misfolding-prone proteins are amyloids, often arranged in a Parallel-In-Register-β-Sheet (PIRIBS) [2] or β-solenoid conformations [3]. Similar folding models have also been proposed for PrPSc, although none of these have been confirmed experimentally. Recent cryo-electron microscopy (cryo-EM) and X-ray fiber-diffraction studies provided evidence that PrPSc is structured as a 4-rung β-solenoid (4RβS) [4, 5]. Here, we combined different experimental data and computational techniques to build the first physically-plausible, atomic resolution model of mouse PrPSc, based on the 4RβS architecture. The stability of this new PrPSc model, as assessed by Molecular Dynamics (MD) simulations, was found to be comparable to that of the prion forming domain of Het-s, a naturally-occurring β-solenoid. Importantly, the 4RβS arrangement allowed the first simulation of the sequence of events underlying PrPC conversion into PrPSc. This study provides the most updated, experimentally-driven and physically-coherent model of PrPSc, together with an unprecedented reconstruction of the mechanism underlying the self-catalytic propagation of prions.
Topics: Animals; Cryoelectron Microscopy; Mice; Models, Molecular; Molecular Dynamics Simulation; PrPC Proteins; PrPSc Proteins; Prions; Protein Conformation; Protein Structure, Quaternary
PubMed: 31295325
DOI: 10.1371/journal.ppat.1007864 -
International Journal of Molecular... Sep 2020Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is... (Review)
Review
Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is typically rich in β-sheet, serves as a template to convert the prion protein into its misfolded conformation. In yeast, the misfolded prion proteins are assembled into amyloid fibers or seeds, which are constantly severed and transmitted to daughter cells. To cure prions in yeast, it is necessary to eliminate all the prion seeds. Multiple mechanisms of curing have been found including inhibiting severing of the prion seeds, gradual dissolution of the prion seeds, asymmetric segregation of the prion seeds between mother and daughter cells during cell division, and degradation of the prion seeds. These mechanisms, achieved by using different protein quality control machinery, are not mutually exclusive; depending on conditions, multiple mechanisms may work simultaneously to achieve curing. This review discusses the various methods that have been used to differentiate between these mechanisms of curing.
Topics: Heat-Shock Proteins; Peptide Termination Factors; Prions; Proteolysis; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 32906758
DOI: 10.3390/ijms21186536 -
Prion 2012The evolutionary origins of vertebrate prion genes had remained elusive until recently when multiple lines of evidence converged to the proposition that members of the...
The evolutionary origins of vertebrate prion genes had remained elusive until recently when multiple lines of evidence converged to the proposition that members of the prion gene family represent an ancient branch of a larger family of ZIP metal ion transporters. (1) A follow-up investigation which explored the mechanism of evolution in more detail led to the surprising conclusion that the emergence of the prion founder gene likely involved the reverse transcription of a spliced transcript of a LIV-1 ZIP predecessor gene. (2) The objective of this perspective is to discuss the possible significance of this reunion of ZIP and prion gene subfamilies for understanding the biology of the prion protein in health and disease. While a recent review article broadly introduced this area of research, (3) the emphasis here is to comment on some of the more pertinent concepts, experimental paradigms, ongoing developments and challenges.
Topics: Animals; Cation Transport Proteins; Evolution, Molecular; Humans; Models, Molecular; Prions; Zinc
PubMed: 22575750
DOI: 10.4161/pri.20196 -
Current Genetics Feb 2018Prions are infectious misfolded proteins that assemble into oligomers and large aggregates, and are associated with neurodegeneration. It is believed that the oligomers... (Review)
Review
Prions are infectious misfolded proteins that assemble into oligomers and large aggregates, and are associated with neurodegeneration. It is believed that the oligomers contribute to cytotoxicity, although genetic and environmental factors have also been shown to have additional roles. The study of the yeast prion [PSI ] has provided valuable insights into how prions form and why they are toxic. Our recent work suggests that SDS-resistant oligomers arise and remodel early during the prion formation process, and lysates containing these newly formed oligomers are infectious. Previous work shows that toxicity is associated with prion formation and this toxicity is exacerbated by deletion of the VPS5 gene. Here, we show that newly made oligomer formation and infectivity of vps5∆ lysates are similar to wild-type strains. However using green fluorescent protein fusions, we observe that the assembly of fluorescent cytoplasmic aggregates during prion formation is different in vps5∆ strains. Instead of large immobile aggregates, vps5∆ strains have an additional population of small mobile foci. We speculate that changes in the cellular milieu in vps5∆ strains may reduce the cell's ability to efficiently recruit and sequester newly formed prion particles into central deposition sites, resulting in toxicity.
Topics: Animals; Disease Susceptibility; Fungal Proteins; Humans; Prions; Protein Aggregates; Protein Aggregation, Pathological; Protein Binding; Protein Multimerization; Yeasts
PubMed: 28856415
DOI: 10.1007/s00294-017-0736-1