Prion protein PrP nucleic acid binding and mobilization implicates retroelements as the replicative component of transmissible spongiform encephalopathy

Lathe, Richard; Darlix, Jean‐Luc

doi:10.1007/s00705-020-04529-2

Cited by 18 publications

(11 citation statements)

References 249 publications

(307 reference statements)

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“…Notably, some pathogenic amyloids have been hypothesized to also play biologically positive roles. For example, Aβ (related to AD) and PrP (associated with transmissible spongiform encephalopathies) were suggested to participate in the antimicrobial defense in brains [ 261 , 262 ]. This indicates that some amyloid-related pathologies could represent a by-product of the functional manifestations of certain amyloids.…”

Section: Discussionmentioning

confidence: 99%

Functional Mammalian Amyloids and Amyloid-Like Proteins

Rubel

Fedotov

Grizel

et al. 2020

Life

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Amyloids are highly ordered fibrous cross-β protein aggregates that are notorious primarily because of association with a variety of incurable human and animal diseases (termed amyloidoses), including Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes (T2D), and prion diseases. Some amyloid-associated diseases, in particular T2D and AD, are widespread and affect hundreds of millions of people all over the world. However, recently it has become evident that many amyloids, termed “functional amyloids,” are involved in various activities that are beneficial to organisms. Functional amyloids were discovered in diverse taxa, ranging from bacteria to mammals. These amyloids are involved in vital biological functions such as long-term memory, storage of peptide hormones and scaffolding melanin polymerization in animals, substrate attachment, and biofilm formation in bacteria and fungi, etc. Thus, amyloids undoubtedly are playing important roles in biological and pathological processes. This review is focused on functional amyloids in mammals and summarizes approaches used for identifying new potentially amyloidogenic proteins and domains.

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Section: Discussionmentioning

confidence: 99%

Functional Mammalian Amyloids and Amyloid-Like Proteins

Rubel

Fedotov

Grizel

et al. 2020

Life

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“…[23][24][25][26][27][28][29][30][31] and a second positively charged patch (aa. [100][101][102][103][104][105][106][107][108][109] were also reported to bind nucleic acids, which is viewed as maybe contributing to TSEs [42,43].…”

Section: Introductionmentioning

confidence: 99%

Membrane Domain Localization and Interaction of the Prion-Family Proteins, Prion and Shadoo with Calnexin

et al. 2021

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The cellular prion protein (PrPC) is renowned for its infectious conformational isoform PrPSc, capable of templating subsequent conversions of healthy PrPCs and thus triggering the group of incurable diseases known as transmissible spongiform encephalopathies. Besides this mechanism not being fully uncovered, the protein’s physiological role is also elusive. PrPC and its newest, less understood paralog Shadoo are glycosylphosphatidylinositol-anchored proteins highly expressed in the central nervous system. While they share some attributes and neuroprotective actions, opposing roles have also been reported for the two; however, the amount of data about their exact functions is lacking. Protein–protein interactions and membrane microdomain localizations are key determinants of protein function. Accurate identification of these functions for a membrane protein, however, can become biased due to interactions occurring during sample processing. To avoid such artifacts, we apply a non-detergent-based membrane-fractionation approach to study the prion protein and Shadoo. We show that the two proteins occupy similarly raft and non-raft membrane fractions when expressed in N2a cells and that both proteins pull down the chaperone calnexin in both rafts and non-rafts. These indicate their possible binding to calnexin in both types of membrane domains, which might be a necessary requisite to aid the inherently unstable native conformation during their lifetime.

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“…The N-terminal IDR, Y145Stop, is broadly classified under the umbrella of RNA-binding proteins due to the presence of two highly conserved polybasic regions containing lysine clusters that have charge complementarity to nucleic acids. 71,72 We next examined the role of RNA in Y145Stop phase separation. The addition of crude t-RNA as low as 100 ng resulted in phase separation as confirmed using turbidity assays and confocal microscopy.…”

Section: Rna Regulates the Phase Behavior Of Y145stopmentioning

confidence: 99%

“…69,70 Additionally, a laser Raman assembly equipped with a microscope allows us to focus the laser beam into the protein-rich, dense, condensed phase of The N-terminal IDR, Y145Stop, is broadly classified under the umbrella of RNA-binding proteins due to the presence of two highly conserved polybasic regions containing lysine clusters that have charge complementarity to nucleic acids. 71,72 We next examined the role of forth. [73][74][75][76][77][78] Together these results suggest that RNA buffers the phase behavior of Y145Stop…”

Section: Vibrational Raman Spectroscopy Captures the Key Conformationmentioning

confidence: 99%

An Intrinsically Disordered Pathological Variant of the Prion Protein Y145Stop Transforms into Self-Templating Amyloids via Liquid-Liquid Phase Separation

Agarwal

Sandeep

Avni

et al. 2021

Preprint

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Biomolecular condensation via liquid-liquid phase separation of intrinsically disordered proteins/regions (IDPs/IDRs) along with other biomolecules is thought to govern critical cellular functions, whereas, aberrant phase transitions are associated with a range of deadly neurodegenerative diseases. Here we show, a naturally occurring pathological truncation variant of the prion protein (PrP) by a mutation of a tyrosine residue at 145 to a stop codon (Y145Stop) yielding a highly disordered N-terminal IDR that spontaneously phase-separates into liquid-like droplets. Phase separation of this N-terminal segment that is rich in positively charged and aromatic residues is promoted by the electrostatic screening and a multitude of other transient, intermolecular, noncovalent interactions. Single-droplet Raman measurements in conjunction with an array of bioinformatic, spectroscopic, microscopic, and mutagenesis studies revealed that the intrinsic disorder and dynamics are retained in the liquid-like condensates. Lower concentrations of RNA promote the phase transition of Y145Stop at low micromolar protein concentrations under physiological condition. Whereas, higher RNA to protein ratios inhibit condensation indicating the role of RNA in modulating the phase behavior of Y145Stop. Highly dynamic liquid-like droplets eventually transform into dynamically-arrested, ordered, β-rich, amyloid-like aggregates via liquid-to-solid transition upon aging. These amyloid-like aggregates formed via phase separation display the self-templating characteristic and are capable of recruiting and autocatalytically converting monomeric Y145Stop into amyloid fibrils. In contrast to this disease-associated intrinsically disordered Y145 truncated variant, the wild-type full-length PrP exhibited a much lower propensity for phase separation and liquid-to-solid maturation into amyloid-like aggregates hinting at a potentially crucial, chaperone-like, protecting role of the globular C-terminal domain that remains largely conserved in vertebrate evolution. Such an intriguing interplay in the modulation of the protein phase behavior will have much broader implications in cell physiology and disease.

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Prion protein PrP nucleic acid binding and mobilization implicates retroelements as the replicative component of transmissible spongiform encephalopathy

Cited by 18 publications

References 249 publications

Functional Mammalian Amyloids and Amyloid-Like Proteins

Functional Mammalian Amyloids and Amyloid-Like Proteins

Membrane Domain Localization and Interaction of the Prion-Family Proteins, Prion and Shadoo with Calnexin

An Intrinsically Disordered Pathological Variant of the Prion Protein Y145Stop Transforms into Self-Templating Amyloids via Liquid-Liquid Phase Separation

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