The G126V Mutation in the Mouse Prion Protein Hinders Nucleation-Dependent Fibril Formation by Slowing Initial Fibril Growth and by Increasing the Critical Concentration

Thody, Sabareesan Ambadi; Udgaonkar, Jayant B.

doi:10.1021/acs.biochem.7b00894

Cited by 22 publications

(20 citation statements)

References 72 publications

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“…The measured lag phase was 47 ± 2 h for the mixing sample. These kinetic analyses are similar to the quantitative comparison of moPrP(G126V) and WT moPrP 72 . These unique dynamic structural features might be responsible for the prion disease-resistance effect of the G127V mutant 20,21 .…”

Section: Discussionsupporting

confidence: 66%

“…In the G127V mutant, the surface electrostatic potential distribution on the region encompassing the α1 and α3 helices is diametrically distinct from those in the WT and the f CJD-associated E200K mutant 26 . The alterations of HuPrP(G127V) in both the geometric packing and electrostatic potential distribution combined with the close atomic distances between SS2 and the disulfide bridge, might prohibit rearrangement of the disulfide bridge, aggregation and fibrillization as previously published results 16,33,54,72 .…”

Section: Discussionmentioning

confidence: 52%

“…The unique geometric packing in the G127V mutant is similar to the protective packing in the V209M mutant 16 and might slow the initial fibrillization rate in a manner similar to that in HuPrP(V209M) 16 and the G126V mutant of the mouse prion protein (moPrP) 72 . The moPrP(G126V) is equivalent to HuPrP(G127V), slows initial fibril growth and increases the critical concentration 72 . The compact geometric packing might also change the local environment of the α2-α3 loop near the α1 helix.…”

Section: Discussionmentioning

confidence: 95%

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

Zheng

Zhang

Wang

et al. 2018

Sci Rep

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Prion diseases are caused by the propagation of misfolded cellular prion proteins (PrPs). A completely prion disease-resistant genotype, V127M129, has been identified in Papua New Guinea and verified in transgenic mice. To disclose the structural basis of the disease-resistant effect of the G127V mutant, we determined and compared the structural and dynamic features of the G127V-mutated human PrP (residues 91–231) and the wild-type PrP in solution. HuPrP(G127V) contains α1, α2 and α3 helices and a stretch-strand (SS) pattern comprising residues Tyr128-Gly131 (SS1) and Val161-Arg164 (SS2), with extending atomic distances between the SS1 and SS2 strands, and a structural rearrangement of the Tyr128 side chain due to steric hindrance of the larger hydrophobic side chain of Val127. The extended α1 helix gets closer to the α2 and α3 helices. NMR dynamics analysis revealed that Tyr128, Gly131 and Tyr163 underwent significant conformational exchanges. Molecular dynamics simulations suggest that HuPrP(G127V) prevents the formation of stable β-sheets and dimers. Unique structural and dynamic features potentially inhibit the conformational conversion of the G127V mutant. This work is beneficial for understanding the molecular mechanisms underlying the complete resistance of the G127V mutant to prion disease and for developing new therapeutics for prion disease.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 95%

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

Zheng

Zhang

Wang

et al. 2018

Sci Rep

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“…In addition, we found no direct microscopic evidence suggesting that new nuclei are produced on the surfaces of amyloid fibrils, raising the question of whether the secondary nucleation is operative in amyloid formation by PrP. A recent study also demonstrated that the classic nucleation-polymerization model is sufficient to reproduce the early-time behavior of amyloid formation by WT PrP (51). Therefore, we currently believe the classic nucleation-polymerization model, which includes only primary nucleation and elongation as the dominant reactions, and attribute the different t lag values shown in Fig.…”

Section: Caveats Of the F-value Analysiscontrasting

confidence: 68%

Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils

Honda

Kuwata

2018

FASEB j.

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Amyloid fibrils are filamentous protein aggregates associated with the pathogenesis of a wide variety of human diseases. The formation of such aggregates typically follows nucleation-dependent kinetics, wherein the assembly and structural conversion of amyloidogenic proteins into oligomeric aggregates (nuclei) is the rate-limiting step of the overall reaction. In this study, we sought to gain structural insights into the oligomeric nuclei of the human prion protein (PrP) by preparing a series of deletion mutants lacking 14-44 of the C-terminal 107 residues of PrP and examined the kinetics and thermodynamics of these mutants in amyloid formation. An analysis of the experimental data using the concepts of the Φ-value analysis indicated that the helix 2 region (residues 168-196) acquires an amyloid-like β-sheet during nucleation, whereas the other regions preserves a relatively disordered structure in the nuclei. This finding suggests that the helix 2 region serves as the nucleation site for the assembly of amyloid fibrils.-Honda, R., Kuwata, K. Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils.

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“…S6 A and B). Rather, des117 aggregation displayed flat concentration dependence, similar to other folded proteins, such as prion protein and light chain amyloid formation (27)(28)(29). This could reflect a strong influence of conformational transition on the kinetics or the presence of alternative aggregation pathways.…”

Section: Anti-amyloid Compound Egcg Slows the Aggregation Of Desminmentioning

confidence: 84%

Desmin Forms Toxic, Seeding Competent Amyloid Aggregates that Persist in Muscle Fibers

Kedia¹,

Arhzaouy²,

Pittman³

et al. 2020

Biophysical Journal

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Desmin-associated myofibrillar myopathy (MFM) has pathologic similarities to neurodegeneration-associated protein aggregate diseases. Desmin is an abundant muscle-specific intermediate filament, and disease mutations lead to its aggregation in cells, animals, and patients. We reasoned that similar to neurodegeneration-associated proteins, desmin itself may form amyloid. Desmin peptides corresponding to putative amyloidogenic regions formed seedingcompetent amyloid fibrils. Amyloid formation was increased when disease-associated mutations were made within the peptide, and this conversion was inhibited by the anti-amyloid compound epigallocatechin-gallate. Moreover, a purified desmin fragment (aa 117 to 348) containing both amyloidogenic regions formed amyloid fibrils under physiologic conditions. Desmin fragment-derived amyloid coaggregated with full-length desmin and was able to template its conversion into fibrils in vitro. Desmin amyloids were cytotoxic to myotubes and disrupted their myofibril organization compared with desmin monomer or other nondesmin amyloids. Finally, desmin fragment amyloid persisted when introduced into mouse skeletal muscle. These data suggest that desmin forms seeding-competent amyloid that is toxic to myofibers. Moreover, small molecules known to interfere with amyloid formation and propagation may have therapeutic potential in MFM.

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The G126V Mutation in the Mouse Prion Protein Hinders Nucleation-Dependent Fibril Formation by Slowing Initial Fibril Growth and by Increasing the Critical Concentration

Cited by 22 publications

References 72 publications

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

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

Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils

Desmin Forms Toxic, Seeding Competent Amyloid Aggregates that Persist in Muscle Fibers

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