Residue-based propensity of aggregation in the Tau amyloidogenic hexapeptides AcPHF6 and AcPHF6

In Alzheimer's disease and related tauopathies, the aggregation of microtubule-associated protein, Tau, into fibrils occurs via the interaction of two hexapeptide motifs PHF* 275 VQIINK 280 and PHF 306 VQIVYK 311 as β-sheets. To understand the role of the constituent amino acids of PHF and PHF*...

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Bibliographic Details
Published in:RSC advances 2020-07, Vol.1 (46), p.27331-27335
Main Authors: Dangi, Abha, Balmik, Abhishek Ankur, Ghorpade, Archana Kisan, Gorantla, Nalini Vijay, Sonawane, Shweta Kishor, Chinnathambi, Subashchandrabose, Marelli, Udaya Kiran
Format: Article
Language:English
Subjects:
Agglomeration
Alanine
Alzheimer's disease
Amino acids
Chemistry
Dichroism
Fluorescence
Glutamine
Morphology
NMR
Nuclear magnetic resonance
Peptides
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Summary:In Alzheimer's disease and related tauopathies, the aggregation of microtubule-associated protein, Tau, into fibrils occurs via the interaction of two hexapeptide motifs PHF* 275 VQIINK 280 and PHF 306 VQIVYK 311 as β-sheets. To understand the role of the constituent amino acids of PHF and PHF* in the aggregation, a set of 12 alanine mutant peptides was synthesized by replacing each amino acid in PHF and PHF* with alanine and they were characterized by nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), transmission electron microscopy (TEM) and ThS/ANS fluorescence assay. Our studies show that while the aggregation was suppressed in most of the alanine mutant peptides, replacement of glutamine by alanine in both PHF and PHF* enhanced the fibrillization. In the alanine mutant peptides of AcPHF6* and AcPHF6, only the peptides with glutamine to alanine substitution show aggregation akin to that of the parent peptides.
ISSN:2046-2069
2046-2069
DOI:10.1039/d0ra03809a