Amyloid nanospheres from polyglutamine rich peptides: assemblage through an intermolecular salt bridge interaction

Mishra, Rahul; Thakur, Ashwani Kumar

doi:10.1039/c4ob02589j

Cited by 14 publications

(17 citation statements)

References 49 publications

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“…Synthetic polyGln peptides were chosen as models for this study (Table ). The polyGln model peptides PGQ 9 A, PGQ 9 I, and PGQ 9 T are point mutants of PGQ 9 Q, which is a model polyGln peptide for inducing β‐hairpin‐fold during aggregation . The first three peptide sequences differs from the PGQ 9 Q peptide with respect to only one amino acid residue at the 18th position across the length of 46 residues (Table ).…”

Section: Resultsmentioning

confidence: 95%

“…The first three peptide sequences differs from the PGQ 9 Q peptide with respect to only one amino acid residue at the 18th position across the length of 46 residues (Table ). Insertion of these residues at this position was found to exert an effect only on the rate of aggregation of PGQ 9 Q and is thus critical in controlling aggregation . However, they do not alter the classical nucleation‐dependent aggregation kinetics of polyGln peptides and the morphologies of their final aggregates formed …”

Section: Resultsmentioning

confidence: 99%

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Insights into the molecular mechanism behind solubilization of amyloidogenic polyglutamine‐containing peptides

Burra

Thakur

2018

Peptide Science

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Synthetic peptides are widely used to understand the protein misfolding and aggregation observed in a diverse group of diseases called systemic amyloidosis and neurodegenerative disorders. The preparation of monomeric solutions of the aggregation‐prone peptides is necessary for achieving a mechanistic understanding efficiently, without compromising any critical step. This study describes novel approaches and mechanisms behind the conversion of otherwise insoluble/sparingly soluble peptides to soluble monomers by trifluoroacetic acid and hexafluoroisopropanol. Although the pretreatment with these solvents results in more or less similar monomers, the mechanism followed to achieve this differs with the solvent. Data show that these solvents aid in the solubility by disrupting the extensive intramolecular and/or intermolecular H‐bond network present in the insoluble peptides.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Insights into the molecular mechanism behind solubilization of amyloidogenic polyglutamine‐containing peptides

Burra

Thakur

2018

Peptide Science

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“…Only polyQ monomers are studied and the inter-molecular interactions among polyQ monomers, which can contribute to aggregation [52], are not included in this study. Additionally, regions flanking the polyQ tract are not considered in this study.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics analysis of the aggregation propensity of polyglutamine segments

2017

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Protein misfolding and aggregation is a pathogenic feature shared among at least ten polyglutamine (polyQ) neurodegenerative diseases. While solvent-solution interaction is a key factor driving protein folding and aggregation, the solvation properties of expanded polyQ tracts are not well understood. By using GPU-enabled all-atom molecular dynamics simulations of polyQ monomers in an explicit solvent environment, this study shows that solvent-polyQ interaction propensity decreases as the lengths of polyQ tract increases. This study finds a predominance in long-distance interactions between residues far apart in polyQ sequences with longer polyQ segments, that leads to significant conformational differences. This study also indicates that large loops, comprised of parallel β-structures, appear in long polyQ tracts and present new aggregation building blocks with aggregation driven by long-distance intra-polyQ interactions. Finally, consistent with previous observations using coarse-grain simulations, this study demonstrates that there is a gain in the aggregation propensity with increased polyQ length, and that this gain is correlated with decreasing ability of solvent-polyQ interaction. These results suggest the modulation of solvent-polyQ interactions as a possible therapeutic strategy for treating polyQ diseases.

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“…Simple polyGln peptides follow nucleation‐dependent polymerization, while with N‐terminal sequence, they exhibit a complex and multistep aggregation mechanism. In such stance, the nonfibrillar oligomeric intermediate is formed via a downhill aggregation mechanism, within which the nucleation of amyloid formation occurs during aggregation …”

Section: Introductionmentioning

confidence: 99%

“…In such stance, the nonfibrillar oligomeric intermediate is formed via a downhill aggregation mechanism, within which the nucleation of amyloid formation occurs during aggregation. [18][19][20][21][22][23][24] A segment of huntingtin, NT 17 Q 37 P 10 K 2 , can undergo aggregation as that of a full-length Htt-exon1 under in vitro conditions. [24,25] The notable molecular interactions that favor aggregation include NT 17 -NT 17 interactions followed by polyGln-polyGln interactions.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of polyglutamine aggregation by SIMILAR huntingtin N‐terminal sequences: Prospective molecules for preclinical evaluation in Huntington's disease

Burra

Thakur

2017

Biopolymers

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The mutant huntingtin protein (mHtt) fragments with expanded polyglutamine sequence forms microscopically visible aggregates in neurons, a hallmark of Huntington's disease (HD). The aggregation process and aggregates are possible targets of therapeutic intervention in HD. Owing to the lack of treatment and cure, the patients die within 15-20 years after the disease onset. Therefore, discovering therapeutic molecules that may either inhibit the aggregation mechanism or downregulate the toxic effects of mHtt are highly needed. This study demonstrates the design and use of peptide inhibitors based on the role played by the N-terminal seventeen amino acid sequence (NT ) of huntingtin fragment in its aggregation. Fug-NT (Fugu), Xen-NT (Xenopus), Dro-NT (Drosophila), Aib-NT , and Pro-NT sequences were tested for their ability to inhibit aggregation. Among them, the first three are the sequence variants of human NT from evolutionarily distant organisms and the latter two are the analogs of human NT -containing aminoisobutyric acid (Aib) and proline (Pro). Four out of five inhibited the aggregation of huntingtin fragment, NT Q P K polypeptide. Data indicate that the physicochemical properties of the inhibitors play a crucial role in exhibiting the inhibitory effect. These inhibitors can be tested in cell and animal models for the preclinical evaluation in the treating of HD.

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Amyloid nanospheres from polyglutamine rich peptides: assemblage through an intermolecular salt bridge interaction

Cited by 14 publications

References 49 publications

Insights into the molecular mechanism behind solubilization of amyloidogenic polyglutamine‐containing peptides

Insights into the molecular mechanism behind solubilization of amyloidogenic polyglutamine‐containing peptides

Molecular dynamics analysis of the aggregation propensity of polyglutamine segments

Inhibition of polyglutamine aggregation by SIMILAR huntingtin N‐terminal sequences: Prospective molecules for preclinical evaluation in Huntington's disease

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