Relationship between Type I and Type II Template Processes: Amyloids and Genome Stability (original) (raw)
Related papers
Prion amyloid structure explains templating: how proteins can be genes
FEMS Yeast Research, 2010
The yeast and fungal prions determine heritable and infectious traits, and are thus genes composed of protein. Most prions are inactive forms of a normal protein as it forms a self-propagating filamentous β -sheet -rich polymer structure called amyloid. Remarkably, a single prion protein sequence can form two or more faithfully inherited prion variants, in effect alleles of these genes. What protein structure explains this protein-based inheritance? Using solid-state NMR, we showed that the infectious amyloids of the prion domains of Ure2p, Sup35p and Rnq1p have an in-register parallel architecture. This structure explains how the amyloid filament ends can template the structure of a new protein as it joins the filament.
Protein inheritance (prions) based on parallel in-register �-sheet amyloid structures
Bioessays, 2008
Most prions (infectious proteins) are self-propagating amyloids (filamentous protein multimers), and have been found in both mammals and fungal species. The prions [URE3] and [PSI+] of yeast are disease agents of Saccharomyces cerevisiae while [Het-s] of Podospora anserina may serve a normal cellular function. The parallel in-register beta-sheet structure shown by prion amyloids makes possible a templating action at the end of filaments which explains the faithful transmission of variant differences in these molecules. This property of self-reproduction, in turn, allows these proteins to act as de facto genes, encoding heritable information.
Protein inheritance (prions) based on parallel in-register β-sheet amyloid structures
BioEssays, 2008
Most prions (infectious proteins) are self-propagating amyloids (filamentous protein multimers), and have been found in both mammals and fungal species. The prions [URE3] and [PSI+] of yeast are disease agents of Saccharomyces cerevisiae while [Het-s] of Podospora anserina may serve a normal cellular function. The parallel in-register beta-sheet structure shown by prion amyloids makes possible a templating action at the end of filaments which explains the faithful transmission of variant differences in these molecules. This property of self-reproduction, in turn, allows these proteins to act as de facto genes, encoding heritable information.
The presence of valine at residue 129 in human prion protein accelerates amyloid formation
FEBS Letters, 2005
Edited by Jesus Avila 12 Abstract The polymorphism at residue 129 of the human 13 PRNP gene modulates disease susceptibility and the clinico-14 pathological phenotypes in human transmissible spongiform 15 encephalopathies. The molecular mechanisms by which the effect 16 of this polymorphism are mediated remain unclear. It has been 17 shown that the folding, dynamics and stability of the physiolog-18 ical, a-helix-rich form of recombinant PrP are not affected by 19 codon 129 polymorphism. Consistent with this, we have recently 20 shown that the kinetics of amyloid formation do not differ be-21 tween protein containing methionine at codon 129 and valine at 22 codon 129 when the reaction is initiated from the a-monomeric 23 PrP C -like state. In contrast, we have shown that the misfolding 24 pathway leading to the formation of b-sheet-rich, soluble oligo-25 mer was favoured by the presence of methionine, compared with 26 valine, at position 129. In the present work, we examine the effect 27 of this polymorphism on the kinetics of an alternative misfolding 28 pathway, that of amyloid formation using partially folded PrP 29 allelomorphs. We show that the valine 129 allelomorph forms 30 amyloids with a considerably shorter lag phase than the methio-31 nine 129 allelomorph both under spontaneous conditions and 32 when seeded with pre-formed amyloid fibres. Taken together, 33 our studies demonstrate that the effect of the codon 129 polymor-34 phism depends on the specific misfolding pathway and on the ini-35 tial conformation of the protein. The inverse propensities of the 36 two allelomorphs to misfold in vitro through the alternative olig-37 omeric and amyloidogenic pathways could explain some aspects 38 of prion diseases linked to this polymorphism such as age at on-39 set and disease incubation time. 40 Ó 2005 Published by Elsevier B.V. on behalf of the Federation of 41 European Biochemical Societies.
2004
Amyloids are self-assembled fibre-like b-rich protein aggregates. Amyloidogenic prion proteins propagate amyloid state in vivo and transmit it via infection or in cell divisions. While amyloid aggregation may occur in the absence of any other proteins, in vivo propagation of the amyloid state requires chaperone helpers. Yeast prion proteins contain prion domains which include distinct aggregation and propagation elements, responsible for these functions. Known aggregation and propagation elements are short in length and composed of relatively simple sequences, indicating possible ancient origin. Prion-like self-assembled structures could be involved in the initial steps of biological compartmentalization in early life.
Nature of cross-seeding barriers of amyloidogenesis
Acta biochimica Polonica, 2012
The epidemics of bovine spongiform encephalopathy (BSE) several decades ago and present epidemics of chronic wasting disease (CWD) among cervids posed a threat of cross-species infections to humans or other animals. Therefore, the question as to the molecular nature of the species barriers to transmissibility of prion diseases is very important. We approached this problem theoretically, first developing a model of template-monomer interaction based on logical and topological grounds and on experimental data about cross-seeding of PrP 23-144 protein orthologs. Further, we propose that the strength of the cross-seeding barriers is proportional to dissimilarity of key amyloidogenic regions of the proteins. This dissimilarity can be measured by dissimilarity function we propose. Scaled on experimental data, this function predicts if cross-seeding can occur between different variants of PrP23-144. The resemblance of PrP23-144 cross-seeding barriers to the barriers of cross-species transm...
Molecular architecture of human prion protein amyloid: A parallel, in-register -structure
Proceedings of the National Academy of Sciences, 2007
Transmissible spongiform encephalopathies (TSEs) represent a group of fatal neurodegenerative diseases that are associated with conformational conversion of the normally monomeric and ␣helical prion protein, PrP C , to the -sheet-rich PrP Sc . This latter conformer is believed to constitute the main component of the infectious TSE agent. In contrast to high-resolution data for the PrP C monomer, structures of the pathogenic PrP Sc or synthetic PrP Sc -like aggregates remain elusive. Here we have used sitedirected spin labeling and EPR spectroscopy to probe the molecular architecture of the recombinant PrP amyloid, a misfolded form recently reported to induce transmissible disease in mice overexpressing an N-terminally truncated form of PrP C . Our data show that, in contrast to earlier, largely theoretical models, the conformational conversion of PrP C involves major refolding of the C-terminal ␣-helical region. The core of the amyloid maps to C-terminal residues from Ϸ160 -220, and these residues form single-molecule layers that stack on top of one another with parallel, in-register alignment of -strands. This structural insight has important implications for understanding the molecular basis of prion propagation, as well as hereditary prion diseases, most of which are associated with point mutations in the region found to undergo a refolding to -structure.
Science, 2000
Prion proteins can serve as genetic elements by adopting distinct physical and functional states that are self-perpetuating and heritable. The critical region of one prion protein, Sup35, is initially unstructured in solution and then forms self-seeded amyloid fibers. We examined in vitro the mechanism by which this state is attained and replicated. Structurally fluid oligomeric complexes appear to be crucial intermediates in de novo amyloid nucleus formation. Rapid assembly ensues when these complexes conformationally convert upon association with nuclei. This model for replicating protein-based genetic information, nucleated conformational conversion, may be applicable to other protein assembly processes.
Extracellular environment modulates the formation and propagation of particular amyloid structures
Molecular Microbiology, 2014
Amyloidogenic proteins, including prions, assemble into multiple forms of structurally distinct fibres. The [PSI + ] prion, endogenous to the yeast Saccharomyces cerevisiae, is a dominantly inherited, epigenetic modifier of phenotypes. [PSI + ] formation relies on the coexistence of another prion, [RNQ + ]. Here, in order to better define the role of amyloid diversity on cellular phenotypes, we investigated how physiological and environmental changes impact the generation and propagation of diverse protein conformations from a single polypeptide. Utilizing the yeast model system, we defined extracellular factors that influence the formation of a spectrum of alternative self-propagating amyloid structures of the Sup35 protein, called [PSI + ] variants. Strikingly, exposure to specific stressful environments dramatically altered the variants of [PSI + ] that formed de novo. Additionally, we found that stress also influenced the association between the [PSI + ] and [RNQ + ] prions in a way that it superceded their typical relationship. Furthermore, changing the growth environment modified both the biochemical properties and [PSI + ]-inducing capabilities of the [RNQ + ] template. These data suggest that the cellular environment contributes to both the generation and the selective propagation of specific amyloid structures, providing insight into a key feature that impacts phenotypic diversity in yeast and the cross-species transmission barriers characteristic of prion diseases.