Direct Identification of Amyloid Peptide Fragments in Human α-Synuclein Based on Consecutive Hydrophobic Amino Acids

Chen, Yongzhu; Peng, Fei; Wu, Kai; Yang, Hao; Qiu, Feng

doi:10.1021/acsomega.0c00979

Cited by 4 publications

(1 citation statement)

References 47 publications

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“…S2 ), supporting that the droplets are filled with amyloids 35 . It is plausible that PK could bind to the insulin amyloid in the droplet since pyrene and its derivatives were shown to bind to various amyloids with hydrophobic interactions 36 , 37 .…”

Section: Resultsmentioning

confidence: 99%

Differences in interaction lead to the formation of different types of insulin amyloid

Mori

Kawakami

Niko

et al. 2022

Sci Rep

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Insulin balls, localized insulin amyloids formed at the site of repeated insulin injections in patients with diabetes, cause poor glycemic control and cytotoxicity. Our previous study has shown that insulin forms two types of amyloids; toxic amyloid formed from the intact insulin ((i)-amyloid) and less-toxic amyloid formed in the presence of the reducing reagent TCEP ((r)-amyloid), suggesting insulin amyloid polymorphism. However, the differences in the formation mechanism and cytotoxicity expression are still unclear. Herein, we demonstrate that the liquid droplets, which are stabilized by electrostatic interactions, appear only in the process of toxic (i)-amyloid formation, but not in the less-toxic (r)-amyloid formation process. The effect of various additives such as arginine, 1,6-hexanediol, and salts on amyloid formation was also examined to investigate interactions that are important for amyloid formation. Our results indicate that the maturation processes of these two amyloids were significantly different, whereas the nucleation by hydrophobic interactions was similar. These results also suggest the difference in the formation mechanism of two different insulin amyloids is attributed to the difference in the intermolecular interactions and could be correlated with the cytotoxicity.

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Section: Resultsmentioning

confidence: 99%

Differences in interaction lead to the formation of different types of insulin amyloid

Mori

Kawakami

Niko

et al. 2022

Sci Rep

View full text Add to dashboard Cite

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Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice

et al. 2022

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Efficiency Enhancement in Peptide Hydrogelators: The Crucial Role of Side Chain Hydrogen Bonding Over Aromatic π–π Interactions

Unnikrishnan,

Das,

Saveri

et al. 2024

Langmuir

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Short peptide assemblies that form supramolecular hydrogels are stabilized by both intermolecular noncovalent interactions among amino acid side chains and hydrogen bonding between peptide backbone amides. Previous research has emphasized the inclusion of aromatic amino acids in short peptide sequences, positing that aromatic π−π interactions contribute significantly to inducing efficient hydrogelation i.e., at low minimum gelation concentrations (MGCs). However, herein, we demonstrate that additional hydrogen bonding interactions from amino acid side chains play a more pivotal role in the efficiency of peptide hydrogelation compared to aromatic π−π interactions. We investigated two sets of Fluorenylmethoxycarbonyl (Fmoc)-functionalized α-synuclein and human islet amyloid peptide fragments [Fmoc-NVGGAVVT (Syn-N) and Fmoc-NFGAIL (IAP-N)], substituting asparagine (N) with phenylalanine (Syn-F/IAP-F), alanine (Syn-A/IAP-A), and glutamine (Syn-Q/IAP-Q). This allowed us to explore the effects of aromatic (π-system), aliphatic (hydrophobic), and hydrogen bonding effects with varying chain lengths on hydrogel formation. Our results reveal that Syn-N and Syn-Q exhibit MGC of 0.03 and 0.05 wt %, respectively, classifying them as super hydrogelators (MGC < 0.1 wt %). These values are 4.0−6.6-fold lower than Syn-F and Syn-A, with Syn-N demonstrating greater efficiency than Syn-Q. Similarly, IAP-N exhibited a substantial decrease in MGC by 8.75, 3.75, and 2.5 folds compared to IAP-A, IAP-F, and IAP-Q, respectively. Experimental evidence and molecular dynamic simulation suggest that −CO-NH 2 of asparagine side chains effectively engaged in hydrogen bonding, thereby immobilizing water molecules at low gelator concentrations. Although glutamine shares similar −CO-NH 2 functionality, its hydrogelation efficiency is less pronounced compared to asparagine, likely due to its longer alkyl chain, which may hinder the formation of a hydrogen bonding network in the self-assembled structure compared to asparagine-containing peptides. These findings offer valuable insights for designing efficient peptide hydrogelators or lowering MGCs by substituting amino acids with asparagine/glutamine in peptide sequences. Additionally, modifying peptide properties through asparagine/glutamine substitution could optimize hydrogel properties for specific applications.

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Direct Identification of Amyloid Peptide Fragments in Human α-Synuclein Based on Consecutive Hydrophobic Amino Acids

Cited by 4 publications

References 47 publications

Differences in interaction lead to the formation of different types of insulin amyloid

Differences in interaction lead to the formation of different types of insulin amyloid

Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice

Efficiency Enhancement in Peptide Hydrogelators: The Crucial Role of Side Chain Hydrogen Bonding Over Aromatic π–π Interactions

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