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

Fatemeh Rahimi Gharemirshamloo ◽  
Ranabir Majumder ◽  
Kourosh Bamdad ◽  
Fateme Frootan ◽  
Cemal Un

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.

2009 ◽  
Vol 33 (11) ◽  
pp. 2300 ◽  
Maurizio Remelli ◽  
Daniela Valensin ◽  
Dimitri Bacco ◽  
Ewa Gralka ◽  
Remo Guerrini ◽  

2020 ◽  
Vol 3 (1) ◽  
Laszlo L. P. Hosszu ◽  
Rebecca Conners ◽  
Daljit Sangar ◽  
Mark Batchelor ◽  
Elizabeth B. Sawyer ◽  

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.

Pathogens ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 482
Simote Foliaki ◽  
Bradley Groveman ◽  
Jue Yuan ◽  
Ryan Walters ◽  
Shulin Zhang ◽  

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

2021 ◽  
Qiuye Li ◽  
Christopher P. Jaroniec ◽  
Witold K. Surewicz

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.

2014 ◽  
Anders S Christensen

In this thesis, a protein structure determination using chemical shifts is presented. The method is implemented in the open source PHAISTOS protein simulation framework. The method combines sampling from a generative model with a coarse-grained force field and an energy function that includes chemical shifts. The method is benchmarked on folding simulations of five small proteins. In four cases the resulting structures are in excellent agreement with experimental data, the fifth case fail likely due to inaccuracies in the energy function. For the Chymotrypsin Inhibitor protein, a structure is determined using only chemical shifts recorded and assigned through automated processes. The CA-RMSD to the experimental X-ray for this structure is 1.1 Å. Additionally, the method is combined with very sparse NOE-restraints and evolutionary distance restraints and tested on several protein structures >100 residues. For Rhodopsin (225 residues) a structure is found at 2.5 Å CA-RMSD from the experimental X-ray structure, and a structure is determined for the Savinase protein (269 residues) with 2.9 Å CA-RMSD from the experimental X-ray structure.

2018 ◽  
Vol 8 (1) ◽  
Zhen Zheng ◽  
Meilan Zhang ◽  
Yongheng Wang ◽  
Rongsheng Ma ◽  
Chenyun Guo ◽  

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