scholarly journals A naturally occurring variant of the human prion protein completely prevents prion disease

Nature ◽  
2015 ◽  
Vol 522 (7557) ◽  
pp. 478-481 ◽  
Author(s):  
Emmanuel A. Asante ◽  
Michelle Smidak ◽  
Andrew Grimshaw ◽  
Richard Houghton ◽  
Andrew Tomlinson ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Naturally Occurring ◽  
Human Prion Protein

scholarly journals Structural effects of the highly protective V127 polymorphism on human prion protein

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Laszlo L. P. Hosszu ◽  
Rebecca Conners ◽  
Daljit Sangar ◽  
Mark Batchelor ◽  
Elizabeth B. Sawyer ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Structural Changes ◽  
Prion Diseases ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Solution Dynamics ◽  
Human Prion Protein ◽  
Prion Transmission

AbstractPrion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP β-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the β2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease.

scholarly journals Strain Specific Resistance to Murine Scrapie Associated with a Naturally Occurring Human Prion Protein Polymorphism at Residue 171

2011 ◽  
Vol 7 (9) ◽  
pp. e1002275 ◽  
Author(s):  
James F. Striebel ◽  
Brent Race ◽  
Kimberly D. Meade-White ◽  
Rachel LaCasse ◽  
Bruce Chesebro
Keyword(s):  
Prion Protein ◽  
Specific Resistance ◽  
Protein Polymorphism ◽  
Naturally Occurring ◽  
Human Prion Protein

scholarly journals Cryo-EM structure of disease-related prion fibrils provides insights into seeding barriers

2021 ◽  
Author(s):  
Qiuye Li ◽  
Christopher P. Jaroniec ◽  
Witold K. Surewicz
Keyword(s):  
High Resolution ◽  
Prion Protein ◽  
Prion Disease ◽  
Amyloid Fibrils ◽  
Prion Diseases ◽  
Protein Aggregates ◽  
Direct Support ◽  
Human Prion Protein ◽  
Structural Insight

One of the least understood aspects of prion diseases is the structure of infectious prion protein aggregates. Here we report a high-resolution cryo-EM structure of amyloid fibrils formed by human prion protein with Y145Stop mutation that is associated with a familial prion disease. This structural insight allows us not only to explain previous biochemical findings, but also provides direct support for the conformational adaptability model of prion transmissibility barriers.

scholarly journals Structural basis for the complete resistance of the human prion protein mutant G127V to prion disease

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Zhen Zheng ◽  
Meilan Zhang ◽  
Yongheng Wang ◽  
Rongsheng Ma ◽  
Chenyun Guo ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Structural Basis ◽  
Complete Resistance ◽  
Human Prion Protein

scholarly journals Multimodal small-molecule screening for human prion protein binders

2020 ◽  
Author(s):  
Andrew G Reidenbach ◽  
Michael F Mesleh ◽  
Dominick Casalena ◽  
Sonia M Vallabh ◽  
Jayme L Dahlin ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Small Molecule ◽  
Neurodegenerative Disorder ◽  
Screening Methods ◽  
Small Molecule Screening ◽  
Differential Scanning Fluorimetry ◽  
Human Prion Protein ◽  
Protein Binders ◽  
Library Selection

ABSTRACTPrion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mM), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. While orthogonal binder discovery methods could yield high affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

scholarly journals Effects of the Pathological E200K Mutation on Human Prion Protein: A Computational screening and Molecular Dynamic approach

2022 ◽  
Author(s):  
Fatemeh Rahimi Gharemirshamloo ◽  
Ranabir Majumder ◽  
Kourosh Bamdad ◽  
Fateme Frootan ◽  
Cemal Un
Keyword(s):  
Protein Structure ◽  
Prion Protein ◽  
Prion Disease ◽  
Protein A ◽  
Protein Structures ◽  
Resistance Mutations ◽  
Pathogenic Potential ◽  
Computational Screening ◽  
E200k Mutation ◽  
Human Prion Protein

Abstract The Human Prion protein gene (PRNP) is mapped to short arm of chromosome 20 (20pter-12). Prion disease is associated with mutations in the Prion Protein encoding gene sequence. The mutations that occur in the prion protein could be divided into two types based on their influence on pathogenic potential: 1. Mutations that cause disease. 2. Disease-resistance mutations. Earlier studies found that the mutation G127V in the PRNP increases protein stability, whereas the mutation E200K, which has the highest mutation rate in the Prion protein, causes Creutzfeldt–Jakob disease (CJD) in humans and induces protein aggregation. We used a variety of bioinformatic algorithms, including SIFT, PolyPhen, I-Mutant, PhD-SNP, and SNP&GO, to predict the association of the E200K mutation with Prion disease. MD simulation is performed and graphs for RMSD, RMSF, Rg, DSSP, PCA, porcupine and FEL are generated to confirm and prove the stability of the wild type and mutant protein structures. The protein is analyzed for aggregation, and the results indicates more fluctuations in the protein structure during the simulation by the E200K mutation, however the G127V mutation makes protein structure stable against aggregation during the simulation.

Aminoacid polymorphism in human prion protein and age at death in inherited prion disease

The Lancet ◽  
1991 ◽  
Vol 337 (8752) ◽  
pp. 1286 ◽  
Author(s):  
H.F Baker ◽  
M Poulter ◽  
T.J Crow ◽  
C.D Frith ◽  
R Lofthouse ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Age At Death ◽  
Human Prion Protein
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