Prion Protein Strain Diversity and Disease Pathology

2019 ◽  
Author(s):  
Saima Zafar ◽  
Neelam Younas ◽  
Mohsin Shafiq ◽  
Inga Zerr
Keyword(s):  
Prion Protein ◽  
Strain Diversity ◽  
Protein Strain

scholarly journals Combining DNP NMR with segmental and specific labeling to study a yeast prion protein strain that is not parallel in-register

2017 ◽  
Vol 114 (14) ◽  
pp. 3642-3647 ◽  
Author(s):  
Kendra K. Frederick ◽  
Vladimir K. Michaelis ◽  
Marc A. Caporini ◽  
Loren B. Andreas ◽  
Galia T. Debelouchina ◽  
...  
Keyword(s):  
Prion Protein ◽  
Long Range ◽  
Isotopic Labeling ◽  
Yeast Prion ◽  
Long Range Interactions ◽  
Intermolecular Contacts ◽  
Protein Strain ◽  
Segmental Isotopic Labeling ◽  
Chemical Shift Degeneracy

The yeast prion protein Sup35NM is a self-propagating amyloid. Despite intense study, there is no consensus on the organization of monomers within Sup35NM fibrils. Some studies point to a β-helical arrangement, whereas others suggest a parallel in-register organization. Intermolecular contacts are often determined by experiments that probe long-range heteronuclear contacts for fibrils templated from a 1:1 mixture of 13C- and 15N-labeled monomers. However, for Sup35NM, like many large proteins, chemical shift degeneracy limits the usefulness of this approach. Segmental and specific isotopic labeling reduce degeneracy, but experiments to measure long-range interactions are often too insensitive. To limit degeneracy and increase experimental sensitivity, we combined specific and segmental isotopic labeling schemes with dynamic nuclear polarization (DNP) NMR. Using this combination, we examined an amyloid form of Sup35NM that does not have a parallel in-register structure. The combination of a small number of specific labels with DNP NMR enables determination of architectural information about polymeric protein systems.

scholarly journals Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids

2018 ◽  
Author(s):  
Hiroki Otaki ◽  
Yuzuru Taguchi ◽  
Noriyuki Nishida
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Prion Protein ◽  
Dynamics Simulation ◽  
Protein Species ◽  
Strain Diversity ◽  
Prion Strains ◽  
Parkinson’S Diseases ◽  
Single Protein ◽  
Β Sheets

AbstractDiversity of prion strains is one of the most mysterious traits of prions because they are mere aggregates of abnormally-folded forms of single protein species, prion protein (PrPSc), without genome. Although the strain-specific properties are hypothesized to be enciphered in the strain-specific structures of PrPSc instead of nucleotide genome, specifically what structure can code the information remains an enigma due to the incompatibility of PrPSc with structural analyses. Although the strain diversity was regarded as unique to prions, recently other disease-associated amyloids of α-synuclein (αSyn) or tau are also reported to have “strains”. As detailed structures of αSyn amyloid are already identified and the properties of mutant αSyn associated with familial Parkinson’s diseases, e.g. A53T, H50Q, and G51D, have been characterized, structure-phenotype relations of this type of amyloid could be investigated by using the αSyn amyloid as a model. Here we intensively investigated the mutant αSyn amyloids by molecular dynamics simulation to characterize influences of mutations on the structures of homo- or hetero-oligomer stacks of the amyloid. The simulations revealed directionality of the amyloid stack, remote effects of the mutations on distant β-sheets, existence of at least two switchable interfaces/amyloid cores, and distinct effects of hetero-oligomerization depending on mutation types. Collectively, those findings implied a possible mechanism of the strain diversity of the amyloids which have multiple in-register parallel β-sheets side-by-side, and support the view that their prion-like properties are inherent in the characteristic structures. We expect that the notion is also applicable to PrPSc.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

CHARACTERISTICS OF ALLELE POOL OF THE ROMANOV SHEEP BREED FOR THE PRION PROTEIN GENE ASSOCIATED WITH GENETIC SUSTAINABILITY TO SCRAPIE

2017 ◽  
Vol 52 (6) ◽  
pp. 1157-1165
Author(s):  
E.A. Gladyr ◽  
◽  
T.E. Deniskova ◽  
V.A. Bagirov ◽  
O.V. Kostyunina ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Gene ◽  
Sheep Breed ◽  
Prion Protein Gene ◽  
Allele Pool

A Unique Functional Feature of the Recombinant Bovine Prion Protein Fragment

2014 ◽  
Author(s):  
Ying Zhai ◽  
Na Li ◽  
Dachuan Zhang ◽  
Qi Li ◽  
Guoping Zhou ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Fragment ◽  
Functional Feature
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