Reduction of a disulfide-constrained oligo-glutamate peptide triggers self-assembly of β 2 -type amyloid fibrils with the chiroptical properties determined by supramolecular chirality

Disulfide bonds prevent aggregation of globular proteins by stabilizing the native state. However, a disulfide bond within a disordered state may accelerate amyloidogenic nucleation by navigating fluctuating polypeptide chains towards an orderly assembly of β-sheets. Here, the self-assembly behavior...

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Bibliographic Details
Published inInternational journal of biological macromolecules Vol. 162; p. 866
Main Authors Dec, Robert, Guza, Marcin, Dzwolak, Wojciech
Format Journal Article
LanguageEnglish
Published Netherlands 01.11.2020
Subjects
Amyloid beta-Peptides - chemistry
Disulfides - chemistry
Glutamic Acid - chemistry
Humans
Kinetics
Peptides - chemistry
Protein Aggregates
Protein Conformation, beta-Strand
Protein Domains
Intrinsic disorder
Self-assembly
Superstructures
Chirality
Fibrils
Homopolypeptides
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Summary:Disulfide bonds prevent aggregation of globular proteins by stabilizing the native state. However, a disulfide bond within a disordered state may accelerate amyloidogenic nucleation by navigating fluctuating polypeptide chains towards an orderly assembly of β-sheets. Here, the self-assembly behavior of Glu-Cys-(Glu) -Cys-Glu peptide (E C ), in which an intrachain disulfide bond is engineered into an amyloidogenic homopolypeptide motif, is investigated. To this end, the Thioflavin T (ThT) fluorescence kinetic assay is combined with infrared spectroscopy, circular dichroism (CD), atomic force microscopy (AFM) and Raman scattering measurements. Regardless of whether the disulfide bond is intact or reduced, E C monomers remain disordered within a broad range of pH. On the other hand, only reduced E C self-assembles into amyloid fibrils with the unique infrared traits indicative of three-center hydrogen bonds involving main-chain carbonyl as a bifurcating acceptor and main-chain NH and side-chain -COOH groups as hydrogen donors: the bonding pattern observed in so-called β -fibrils. AFM analysis of β -E C reveals tightly packed rectangular superstructures whose presence coincides with strong chiroptical properties. Our findings suggest that formation of chiral amyloid superstructures may be a generic process accessible to various substrates, and that the fully extended conformation of a poly-Glu chain is a condition sine qua non for self-assembly of β -fibrils.
ISSN:1879-0003