scholarly journals Probing the Role of PrP Repeats in Conformational Conversion and Amyloid Assembly of Chimeric Yeast Prions

2007 ◽  
Vol 282 (47) ◽  
pp. 34204-34212 ◽  
Author(s):  
Jijun Dong ◽  
Jesse D. Bloom ◽  
Vladimir Goncharov ◽  
Madhuri Chattopadhyay ◽  
Glenn L. Millhauser ◽  
...  
Keyword(s):  
Yeast Prions ◽  
Amyloid Assembly ◽  
Conformational Conversion

Delineating the Role of Helical Intermediates in Natively Unfolded Polypeptide Amyloid Assembly and Cytotoxicity

2015 ◽  
Vol 54 (48) ◽  
pp. 14383-14387 ◽  
Author(s):  
Carole Anne De Carufel ◽  
Noé Quittot ◽  
Phuong Trang Nguyen ◽  
Steve Bourgault
Keyword(s):  
Natively Unfolded ◽  
Amyloid Assembly

scholarly journals Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Hideyuki Hara ◽  
Hironori Miyata ◽  
Nandita Rani Das ◽  
Junji Chida ◽  
Tatenobu Yoshimochi ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Prion Diseases ◽  
Spongiform Encephalopathy ◽  
Wild Type ◽  
Jakob Disease ◽  
Function Relationship ◽  
Different Strains ◽  
Conformational Conversion

ABSTRACTConformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrPCinto PrPScafter infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/Prnp0/0mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrPScΔOR in their brains. We show here that Tg(PrPΔOR)/Prnp0/0mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrPScΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrPCinto PrPScafter infection with BSE prions. However, Tg(PrPΔOR)/Prnp0/0mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrPScΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/Prnp0/0mice than PrPScin control wild-type mice. Taken together, these results indicate that the OR region of PrPCcould play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions.IMPORTANCEStructure-function relationship studies of PrPCconformational conversion into PrPScare worthwhile to understand the mechanism of the conversion of PrPCinto PrPSc. We show here that, by inoculating Tg(PrPΔOR)/Prnp0/0mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrPCinto PrPScafter infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrPScΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrPScΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrPCinto PrPScafter infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.

scholarly journals Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers

2021 ◽  
Author(s):  
Nikolaos N Louros ◽  
Meine Ramakers ◽  
Emiel Michiels ◽  
Katerina Konstantoulea ◽  
Chiara Morelli ◽  
...  
Keyword(s):  
Sequence Homology ◽  
Protein Sequences ◽  
Sequence Specificity ◽  
Structural Mechanism ◽  
Structural Rules ◽  
Amyloidogenic Proteins ◽  
Systematic Understanding ◽  
Fibril Morphology ◽  
Amyloid Assembly

Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly. Using structure-based thermodynamic calculations and extensive experimental validation, we performed a comprehensive exploration of the defining role of sequence promiscuity in amyloid interactions. Using this knowledge, we demonstrate, using tau as a model system, that predicted cross-interactions driven by sequence homology indeed can modify nucleation, fibril morphology, kinetic assembly and cellular spreading of aggregates. We also find that these heterotypic amyloid interactions can result in the mis-localisation of brain-expressed protein sequences with prevalent activities in neurodegenerative disorders. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression.

scholarly journals Cellular Biology of Prion Diseases

1999 ◽  
Vol 12 (3) ◽  
pp. 429-444 ◽  
Author(s):  
David A. Harris
Keyword(s):  
Information Transfer ◽  
Cellular Localization ◽  
Prion Diseases ◽  
Proteolytic Processing ◽  
Biological Information ◽  
Cell Culture Systems ◽  
Membrane Attachment ◽  
Conformational Conversion ◽  
Prion Hypothesis

Prion diseases are fatal neurodegenerative disorders of humans and animals that are important because of their impact on public health and because they exemplify a novel mechanism of infectivity and biological information transfer. These diseases are caused by conformational conversion of a normal host glycoprotein (PrPC) into an infectious isoform (PrPSc) that is devoid of nucleic acid. This review focuses on the current understanding of prion diseases at the cell biological level. The characteristics of the diseases are introduced, and a brief history and description of the prion hypothesis are given. Information is then presented about the structure, expression, biosynthesis, and possible function of PrPC, as well as its posttranslational processing, cellular localization, and trafficking. The latest findings concerning PrPSc are then discussed, including cell culture systems used to generate this pathogenic isoform, the subcellular distribution of the protein, its membrane attachment, proteolytic processing, and its kinetics and sites of synthesis. Information is also provided on molecular models of the PrPC→PrPSc conversion reaction and the possible role of cellular chaperones. The review concludes with suggestions of several important avenues for future investigation.

scholarly journals The role of the IT-state in D76N β2-microglobulin amyloid assembly: A crucial intermediate or an innocuous bystander?

2020 ◽  
Vol 295 (35) ◽  
pp. 12474-12484 ◽  
Author(s):  
Hugh I. Smith ◽  
Nicolas Guthertz ◽  
Emma E. Cawood ◽  
Roberto Maya-Martinez ◽  
Alexander L. Breeze ◽  
...  
Keyword(s):  
Amino Acids ◽  
Single Amino Acid ◽  
Folding Intermediate ◽  
Exposed Site ◽  
Aggregation Propensity ◽  
Amyloid Disease ◽  
Aggregation Rate ◽  
Amyloid Assembly

The D76N variant of human β2-microglobulin (β2m) is the causative agent of a hereditary amyloid disease. Interestingly, D76N-associated amyloidosis has a distinctive pathology compared with aggregation of WT-β2m, which occurs in dialysis-related amyloidosis. A folding intermediate of WT-β2m, known as the IT-state, which contains a nonnative trans Pro-32, has been shown to be a key precursor of WT-β2m aggregation in vitro. However, how a single amino acid substitution enhances the rate of aggregation of D76N-β2m and gives rise to a different amyloid disease remained unclear. Using real-time refolding experiments monitored by CD and NMR, we show that the folding mechanisms of WT- and D76N-β2m are conserved in that both proteins fold slowly via an IT-state that has similar structural properties. Surprisingly, however, direct measurement of the equilibrium population of IT using NMR showed no evidence for an increased population of the IT-state for D76N-β2m, ruling out previous models suggesting that this could explain its enhanced aggregation propensity. Producing a kinetically trapped analog of IT by deleting the N-terminal six amino acids increases the aggregation rate of WT-β2m but slows aggregation of D76N-β2m, supporting the view that although the folding mechanisms of the two proteins are conserved, their aggregation mechanisms differ. The results exclude the IT-state as the origin of the rapid aggregation of D76N-β2m, suggesting that other nonnative states must cause its high aggregation rate. The results highlight how a single substitution at a solvent-exposed site can affect the mechanism of aggregation and the resulting disease.

scholarly journals Appearance of annular ring-like intermediates during amyloid fibril formation from human serum albumin

2015 ◽  
Vol 17 (35) ◽  
pp. 22862-22871 ◽  
Author(s):  
Shruti Arya ◽  
Arpana Kumari ◽  
Vijit Dalal ◽  
Mily Bhattacharya ◽  
Samrat Mukhopadhyay
Keyword(s):  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Amyloid Fibril ◽  
Temporal Evolution ◽  
Fibril Formation ◽  
Amyloid Fibril Formation ◽  
Amyloid Assembly ◽  
Conformational Conversion ◽  
Β Sheet

A profound conformational conversion coupled with the temporal evolution of morphologically-distinct ring-like nanoscopic intermediates were monitored during the amyloid assembly of human serum albumin into β-sheet-rich fibrils.

scholarly journals Role of ADAMs in the Ectodomain Shedding and Conformational Conversion of the Prion Protein

2009 ◽  
Vol 284 (34) ◽  
pp. 22590-22600 ◽  
Author(s):  
David R. Taylor ◽  
Edward T. Parkin ◽  
Sarah L. Cocklin ◽  
James R. Ault ◽  
Alison E. Ashcroft ◽  
...  
Keyword(s):  
Prion Protein ◽  
Ectodomain Shedding ◽  
Conformational Conversion

scholarly journals The role of pre-existing aggregates in Hsp104-dependent polyglutamine aggregate formation and epigenetic change of yeast prions

2004 ◽  
Vol 9 (8) ◽  
pp. 685-696 ◽  
Author(s):  
Yoko Kimura ◽  
Sumiko Koitabashi ◽  
Akira Kakizuka ◽  
Takashi Fujita
Keyword(s):  
Epigenetic Change ◽  
Aggregate Formation ◽  
Yeast Prions
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