Amyloid aggregates of the HET-s prion protein are infectious

Maddelein, Marie‐Lise; Reis, Suzana Dos; Duvezin-Caubet, Stéphane; Coulary‐Salin, Bénédicte; Saupe, Sven J.

doi:10.1073/pnas.072199199

Cited by 265 publications

(202 citation statements)

References 38 publications

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“…In case of mammals, in response to viral infection pattern recognition receptors RIG-1 and NLRP-3 induce prion-like conformational switching and polymerization of their adaptors MAVS and ASC thereby enabling downstream signaling cascade resulting in cytokine secretion and cell death. An analogous phenomenon is observed in yeast cells, where NWD2 protein induces similar conversion of downstream adaptor protein HET-S/s 198 . These fibers are self propagating and heritable but are notably different from conventional prions in that the fibers do not have the typical cross-b structures of amyloid fibers, but instead retain a helical conformation.…”

Section: Reversible Amyloid Assembly Mediated By Prion Domains?mentioning

confidence: 56%

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Sudhakaran

Ramaswami

2016

RNA Biology

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Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs function in synapse specific plasticity underlying LTM.

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Section: Reversible Amyloid Assembly Mediated By Prion Domains?mentioning

confidence: 56%

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Sudhakaran

Ramaswami

2016

RNA Biology

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“…In addition, [Het-s] has been identified as a prion of the filamentous fungus Podospora anserina [16,17]. The relative simplicity and tractability of yeast and other fungal systems has allowed convincing proof of the protein-only hypothesis for Het-s [18], Sup35 [19,20] and Ure2 [21].…”

Section: Overviewmentioning

confidence: 94%

The yeast prion protein Ure2: Structure, function and folding

Lian

Jiang

Zhang

et al. 2006

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The Saccharomyces cerevisiae protein Ure2 functions as a regulator of nitrogen metabolism and as a glutathione-dependent peroxidase. Ure2 also has the characteristics of a prion, in that it can undergo a heritable conformational change to an aggregated state; the prion form of Ure2 loses the regulatory function, but the enzymatic function appears to be maintained. A number of factors are found to affect the prion properties of Ure2, including mutation and expression levels of molecular chaperones, and the effect of these factors on structure and stability are being investigated. The relationship between structure, function and folding for the yeast prion Ure2 are discussed.

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“…Sequence specific determination of regular secondary structure and its topology in HET-s (218-289) fibrils. a,b, Fast HMQC-spectra of homogenously 15 N-labeled HET-s(218-289) in d 6 -DMSO containing 0.1 % d 1 -TFA, corresponding to fully protonated (a), and partially hydrogen exchanged (b) amyloid fibrils. Sequence specific chemical shift assignments are labeled.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Correlation of structural elements and infectivity of the HET-s prion

Ritter¹,

Maddelein²,

Siemer³

et al. 2005

Nature

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Prions are believed to be infectious self-propagating polymers of otherwise soluble host-encoded proteins 1,2 . This concept is now strongly supported by the recent findings that amyloid fibrils of recombinant prion proteins from yeast 3-5 , Podospora anserina 6 , and mammals 7 can induce prion phenotypes in the corresponding hosts. However, the structural basis of prion infectivity remains largely elusive because acquisition of atomic resolution structural properties of amyloid fibrils represents a largely unsolved technical challenge. HET-s, the prion protein of P. anserina, contains a C-terminal prion domain comprising residues 218-289. Amyloid fibrils of are necessary and sufficient for the induction and propagation of prion infectivity 6 . Here, we have used fluorescence studies, quenched hydrogen exchange NMR and solid state NMR to determine the sequence specific positions of secondary structure elements of amyloid fibrils of . This revealed four β-strands constituted by two pseudo repeat sequences, each forming a β-strandturn-β-strand motif. We show that this conformation is the functional and infectious entity of the HET-s prion by using a structure-based mutagenesis approach. These results correlate for the first time distinct structural elements with prion infectivity.The prion form of the protein HET-s is involved in a programmed cell death phenomenon termed heterokaryon incompatibility 8,9 . This reaction occurs in filamentous fungi when cells of incompatible genotype fuse and form a mixed cell. In P. anserina, two incompatible genotypes, called het-s and het-S, encode for the proteins HET-s and HET-S. They are both 289 amino acids long and differ in only 13 residues 10 . However, only HET-s can form a prion 11 : P. anserina cells expressing the HET-s protein exist either in a prion state called [Hets] Correspondence and requests for materials should be addressed to R.R. (e-mail: riek@salk.edu).. $ these authors contributed equally to this work.Supplementary Information accompanies the paper on Nature's website (http://www.nature.com). (Fig. 1a) contained one assigned cross-peak for each backbone amide of with the exception of 289, enabling a residuespecific determination of the hydrogen exchange rates. Upon exchange in D 2 O buffer for 6 weeks the intensity of about 45% of the resonances was significantly reduced or absent from the spectrum (Fig. 1b). This suggested that the corresponding amides have undergone exchange with solvent deuterons, which are not visible in this experiment. NIH Public AccessThe hydrogen exchange was followed over a total period of 3 months. All residues displayed a mono-exponential decay (Fig. S1) indicating that the structure of the fibrils was well defined and homogeneous. The summarized hydrogen exchange data (Fig. 1e) show that due to exchange rates faster than 5·h -1 , the 8 N-terminal residues, the 5 C-terminal residues and residues 247-261 are only weakly or not protected and may therefore be conformationally disordered. Four segments were observed that d...

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Amyloid aggregates of the HET-s prion protein are infectious

Cited by 265 publications

References 38 publications

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

The yeast prion protein Ure2: Structure, function and folding

Correlation of structural elements and infectivity of the HET-s prion

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