Water-Soluble Tripeptide Aβ (9−11) Forms Amyloid-Like Fibrils and Exhibits Neurotoxicity

Naskar, Jishu; Drew, Michael G. B.; Deb, Ishani; Das, Sumantra; Banerjee, Arindam

doi:10.1021/ol8007217

Cited by 27 publications

(20 citation statements)

References 29 publications

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“…We noticed that the peptide sequence, GYE, found at positions 9–11 in amyloid β 1–42 occurs in several thermophilic proteins and their mesophilic homologs. The tripeptide GYE from Aβ 1–42 is the smallest peptide known to form amyloid fibrils (Naskar et al 47…”

Section: Resultsmentioning

confidence: 99%

“…If thermophiles are more ancient than the mesophiles, can we trace some of the well‐known aggregating peptide sequences to their thermophilic ancestors? By scanning a library of experimentally proven aggregating peptide sequences against the sequences of the thermophilic proteins, GYE, the smallest peptide shown to form amyloid‐like fibrils47 and found in Aβ peptide sequence, was detected in several thermophilic proteins from Pyrococcus furiosus, Pyrococcus horikoshii, Methanobacterium thermoautotrophicum, Sulfolobus solfataricus, Aquifex aeolicus, Bacillus sphaericus, B. stearothermophilus, Clostridium thermocellum, T. maritima , and T. thermophilus . In this study, we are limited by the available peptide sequences proven to form amyloid‐like fibrils.…”

Section: Discussionmentioning

confidence: 99%

“…Three experimentally proven amyloid‐like fibril forming peptide sequences were also detected in the thermophilic proteins. These are GYE from amyloid β peptide,47 designed tetrapeptide KVVE,48 and a hexpeptide VSFEIV from the Waltz training set 30. However, the thermophilic protein monomers have greater ability to “stow away” the APRs in hydrophobic cores where they are protected from solvent exposure.…”

Section: Introductionmentioning

confidence: 99%

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How do thermophilic proteins resist aggregation?

Thangakani¹,

Kumar²,

Velmurugan³

et al. 2012

Proteins

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Aggregation is an ancient threat that must be overcome by proteins from all organisms to maintain their native functional states. This is essential for the maintenance of metabolic flux and viability of their cellular machineries. Here, we compare the aggregation-resistance strategies adapted by the thermophilic proteins and their mesophilic homologs using a dataset of 373 protein families. Like their mesophilic homologs, the thermophilic protein sequences also contain potential aggregation prone regions (APRs), capable of forming cross-β motif and amyloid-like fibrils. Tetrapeptide and hexapeptide amyloid-like fibril forming sequence patterns and experimentally proven amyloid-like fibril forming peptide sequences were also detected in the thermophilic proteins. Both the thermophilic and the mesophilic proteins use similar strategies to resist aggregation. However, the thermophilic proteins show superior utilization of these strategies. The thermophilic protein monomers show greater ability to "stow away" the APRs in the hydrophobic cores to protect them from solvent exposure. The thermophilic proteins are also better at gatekeeping the APRs by surrounding them with charged residues (Asp, Glu, Lys, and Arg) and Pro to a greater extent. While thermophilic and mesophilic proteins in our dataset are highly homologous and show strong overall sequence conservation, the APRs are not conserved between the homologs. These findings indicate that evolution is working to avoid amyloidogenic regions in proteins. Our results are also consistent with the observation that thermophilic cells often accumulate small molecule osmolytes capable of stabilizing their proteins and other macromolecules. This study has important implications for rational design and formulation of therapeutic proteins and antibodies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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How do thermophilic proteins resist aggregation?

Thangakani¹,

Kumar²,

Velmurugan³

et al. 2012

Proteins

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“…The smallest length for a peptide that forms amyloid fibrils is three amino acid residues[43]. Tetra-peptides have also been shown to form amyloid-fibrils [12].…”

Section: Discussionmentioning

confidence: 99%

Distinct position-specific sequence features of hexa-peptides that form amyloid-fibrils: application to discriminate between amyloid fibril and amorphous β-aggregate forming peptide sequences

et al. 2013

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BackgroundComparison of short peptides which form amyloid-fibrils with their homologues that may form amorphous β-aggregates but not fibrils, can aid development of novel amyloid-containing nanomaterials with well defined morphologies and characteristics. The knowledge gained from the comparative analysis could also be applied towards identifying potential aggregation prone regions in proteins, which are important for biotechnology applications or have been implicated in neurodegenerative diseases. In this work we have systematically analyzed a set of 139 amyloid-fibril hexa-peptides along with a highly homologous set of 168 hexa-peptides that do not form amyloid fibrils for their position-wise as well as overall amino acid compositions and averages of 49 selected amino acid properties.ResultsAmyloid-fibril forming peptides show distinct preferences and avoidances for amino acid residues to occur at each of the six positions. As expected, the amyloid fibril peptides are also more hydrophobic than non-amyloid peptides. We have used the results of this analysis to develop statistical potential energy values for the 20 amino acid residues to occur at each of the six different positions in the hexa-peptides. The distribution of the potential energy values in 139 amyloid and 168 non-amyloid fibrils are distinct and the amyloid-fibril peptides tend to be more stable (lower total potential energy values) than non-amyloid peptides. The average frequency of occurrence of these peptides with lower than specific cutoff energies at different positions is 72% and 50%, respectively. The potential energy values were used to devise a statistical discriminator to distinguish between amyloid-fibril and non-amyloid peptides. Our method could identify the amyloid-fibril forming hexa-peptides to an accuracy of 89%. On the other hand, the accuracy of identifying non-amyloid peptides was only 54%. Further attempts were made to improve the prediction accuracy via machine learning. This resulted in an overall accuracy of 82.7% with the sensitivity and specificity of 81.3% and 83.9%, respectively, in 10-fold cross-validation method.ConclusionsAmyloid-fibril forming hexa-peptides show position specific sequence features that are different from those which may form amorphous β-aggregates. These positional preferences are found to be important features for discriminating amyloid-fibril forming peptides from their homologues that don't form amyloid-fibrils.

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“…NH 2 -GYE-OH, forms amyloid-like fibrils in aqueous solution. 456 MTT assays indicate that the peptide is toxic to neurons.…”

Section: Fragmentsmentioning

confidence: 99%

The Amyloid Beta Peptide: A Chemist’s Perspective. Role in Alzheimer’s and Fibrillization

2012

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Water-Soluble Tripeptide Aβ (9−11) Forms Amyloid-Like Fibrils and Exhibits Neurotoxicity

Cited by 27 publications

References 29 publications

How do thermophilic proteins resist aggregation?

How do thermophilic proteins resist aggregation?

Distinct position-specific sequence features of hexa-peptides that form amyloid-fibrils: application to discriminate between amyloid fibril and amorphous β-aggregate forming peptide sequences

The Amyloid Beta Peptide: A Chemist’s Perspective. Role in Alzheimer’s and Fibrillization

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