A review on the salt bridge ASP177-ARG163 (O–N) of wild-type rabbit prion protein

Zhang, Jiapu; Wang, Feng

doi:10.1080/07391102.2015.1064832

Cited by 6 publications

(4 citation statements)

References 49 publications

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“…The generation of transgenic rabbits expressing ovine PrP and their successful infection with scrapie prions definitively highlighted that the amino acid sequence of rabbit PrP C was responsible for the low susceptibility of rabbits to prion infections (14). Although rabbit PrP C has been studied in detail to identify distinctive structural elements that explain its low susceptibility to prion-like misfolding (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), the key elements or amino acid residues causing this behavior remain unknown.…”

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confidence: 99%

In Vitro Approach To Identify Key Amino Acids in Low Susceptibility of Rabbit Prion Protein to Misfolding

Eraña

Fernández‐Borges

Elezgarai

et al. 2017

J Virol

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Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of rare progressive neurodegenerative disorders caused by an abnormally folded prion protein (PrP). This is capable of transforming the normal cellular prion protein (PrP) into new infectious PrP Interspecies prion transmissibility studies performed by experimental challenge and the outbreak of bovine spongiform encephalopathy that occurred in the late 1980s and 1990s showed that while some species (sheep, mice, and cats) are readily susceptible to TSEs, others are apparently resistant (rabbits, dogs, and horses) to the same agent. To study the mechanisms of low susceptibility to TSEs of certain species, the mouse-rabbit transmission barrier was used as a model. To identify which specific amino acid residues determine high or low susceptibility to PrP propagation, protein misfolding cyclic amplification (PMCA), which mimics PrP-to-PrP conversion with accelerated kinetics, was used. This allowed amino acid substitutions in rabbit PrP and accurate analysis of misfolding propensities. Wild-type rabbit recombinant PrP could not be misfolded into a protease-resistant self-propagating isoform despite seeding with at least 12 different infectious prions from diverse origins. Therefore, rabbit recombinant PrP mutants were designed to contain every single amino acid substitution that distinguishes rabbit recombinant PrP from mouse recombinant PrP. Key amino acid residue substitutions were identified that make rabbit recombinant PrP susceptible to misfolding, and using these, protease-resistant misfolded recombinant rabbit PrP was generated. Additional studies characterized the mechanisms by which these critical amino acid residue substitutions increased the misfolding susceptibility of rabbit PrP. Prion disorders are invariably fatal, untreatable diseases typically associated with long incubation periods and characteristic spongiform changes associated with neuronal loss in the brain. Development of any treatment or preventative measure is dependent upon a detailed understanding of the pathogenesis of these diseases, and understanding the mechanism by which certain species appear to be resistant to TSEs is critical. Rabbits are highly resistant to naturally acquired TSEs, and even under experimental conditions, induction of clinical disease is not easy. Using recombinant rabbit PrP as a model, this study describes critical molecular determinants that confer this high resistance to transmissible spongiform encephalopathies.

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confidence: 99%

In Vitro Approach To Identify Key Amino Acids in Low Susceptibility of Rabbit Prion Protein to Misfolding

Eraña

Fernández‐Borges

Elezgarai

et al. 2017

J Virol

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“…An endeavor to systematically characterize the differences in the secondary structure and in the flexibility of the protein for a large number of PrP species through molecular dynamics simulations was attempted by Zhang (2018) . These studies identified a salt bridge between R164 and D178 ( Zhang and Wang, 2016 ) as important for the β2-α2 loop stability.…”

Section: Conformational Dynamics Of Prp Probed By Molecular Modelingmentioning

confidence: 99%

Insight From Animals Resistant to Prion Diseases: Deciphering the Genotype – Morphotype – Phenotype Code for the Prion Protein

Myers

Cembran

Fernández-Fúnez

2020

Front. Cell. Neurosci.

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Prion diseases are a group of neurodegenerative diseases endemic in humans and several ruminants caused by the misfolding of native prion protein (PrP) into pathological conformations. Experimental work and the mad-cow epidemic of the 1980s exposed a wide spectrum of animal susceptibility to prion diseases, including a few highly resistant animals: horses, rabbits, pigs, and dogs/canids. The variable susceptibility to disease offers a unique opportunity to uncover the mechanisms governing PrP misfolding, neurotoxicity, and transmission. Previous work indicates that PrP-intrinsic differences (sequence) are the main contributors to disease susceptibility. Several residues have been cited as critical for encoding PrP conformational stability in prion-resistant animals, including D/E159 in dog, S167 in horse, and S174 in rabbit and pig PrP (all according to human numbering). These amino acids alter PrP properties in a variety of assays, but we still do not clearly understand the structural correlates of PrP toxicity. Additional insight can be extracted from comparative structural studies, followed by molecular dynamics simulations of selected mutations, and testing in manipulable animal models. Our working hypothesis is that protective amino acids generate more compact and stable structures in a C-terminal subdomain of the PrP globular domain. We will explore this idea in this review and identify subdomains within the globular domain that may hold the key to unravel how conformational stability and disease susceptibility are encoded in PrP.

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“…Studies focused on the CT3DD uncovered a key role for the solvent exposure of the highly conserved Y169 in stabilizing the 3 10 -turn ( Huang and Caflisch, 2015a , b ; Caldarulo et al, 2017 ). Lastly, the systematic characterization of the secondary structures and flexibility for many PrP species identified a critical salt bridge between R164 and D178 for the β2-α2 loop stability ( Zhang and Wang, 2016 ; Zhang, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic determinants of prion protein neurotoxicity in Drosophila: from sequence to (dys)function

Cembran

Fernández-Fúnez

2023

Front. Mol. Neurosci.

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Prion diseases are fatal brain disorders characterized by deposition of insoluble isoforms of the prion protein (PrP). The normal and pathogenic structures of PrP are relatively well known after decades of studies. Yet our current understanding of the intrinsic determinants regulating PrP misfolding are largely missing. A 3D subdomain of PrP comprising the β2-α2 loop and helix 3 contains high sequence and structural variability among animals and has been proposed as a key domain regulating PrP misfolding. We combined in vivo work in Drosophila with molecular dynamics (MD) simulations, which provide additional insight to assess the impact of candidate substitutions in PrP from conformational dynamics. MD simulations revealed that in human PrP WT the β2-α2 loop explores multiple β-turn conformations, whereas the Y225A (rabbit PrP-like) substitution strongly favors a 310-turn conformation, a short right-handed helix. This shift in conformational diversity correlates with lower neurotoxicity in flies. We have identified additional conformational features and candidate amino acids regulating the high toxicity of human PrP and propose a new strategy for testing candidate modifiers first in MD simulations followed by functional experiments in flies. In this review we expand on these new results to provide additional insight into the structural and functional biology of PrP through the prism of the conformational dynamics of a 3D domain in the C-terminus. We propose that the conformational dynamics of this domain is a sensitive measure of the propensity of PrP to misfold and cause toxicity. This provides renewed opportunities to identify the intrinsic determinants of PrP misfolding through the contribution of key amino acids to different conformational states by MD simulations followed by experimental validation in transgenic flies.

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A review on the salt bridge ASP177-ARG163 (O–N) of wild-type rabbit prion protein

Cited by 6 publications

References 49 publications

In Vitro Approach To Identify Key Amino Acids in Low Susceptibility of Rabbit Prion Protein to Misfolding

In Vitro Approach To Identify Key Amino Acids in Low Susceptibility of Rabbit Prion Protein to Misfolding

Insight From Animals Resistant to Prion Diseases: Deciphering the Genotype – Morphotype – Phenotype Code for the Prion Protein

Intrinsic determinants of prion protein neurotoxicity in Drosophila: from sequence to (dys)function

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