Dataset Information

Cross-α/β polymorphism of PSMα3 fibrils.

ABSTRACT: The formation of ordered cross-β amyloid protein aggregates is associated with a variety of human disorders. While conventional infrared methods serve as sensitive reporters of the presence of these amyloids, the recently discovered amyloid secondary structure of cross-α fibrils presents new questions and challenges. Herein, we report results using Fourier transform infrared spectroscopy and two-dimensional infrared spectroscopy to monitor the aggregation of one such cross-α-forming peptide, phenol soluble modulin alpha 3 (PSMα3). Phenol soluble modulins (PSMs) are involved in the formation and stabilization of Staphylococcus aureus biofilms, making sensitive methods of detecting and characterizing these fibrils a pressing need. Our experimental data coupled with spectroscopic simulations reveals the simultaneous presence of cross-α and cross-β polymorphs within samples of PSMα3 fibrils. We also report a new spectroscopic feature indicative of cross-α fibrils.

SUBMITTER: Cracchiolo OM

PROVIDER: S-EPMC8812551 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Cross-α/β polymorphism of PSMα3 fibrils.

Cracchiolo Olivia M OM Edun Dean N DN Betti Vincent M VM Goldberg Jacob M JM Serrano Arnaldo L AL

Proceedings of the National Academy of Sciences of the United States of America 20220201 5

The formation of ordered cross-β amyloid protein aggregates is associated with a variety of human disorders. While conventional infrared methods serve as sensitive reporters of the presence of these amyloids, the recently discovered amyloid secondary structure of cross-α fibrils presents new questions and challenges. Herein, we report results using Fourier transform infrared spectroscopy and two-dimensional infrared spectroscopy to monitor the aggregation of one such cross-α-forming peptide, phe ...[more]

PMID: 35078934

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Project description:Functional amyloids are abundant in living organisms from prokaryotes to eukaryotes playing diverse biological roles. In contrast to the irreversible aggregation of most known pathological amyloids, we postulate that naturally-occurring functional amyloids are reversible under evolutionary pressure to be able to modulate the fibrillization process, reuse the composite peptides, or perform their biological functions. β-Endorphin, an endogenous opioid peptide hormone, forms such kinds of reversible amyloid fibrils in secretory granules for efficient storage and returns to the functional state of monomers upon release into the blood. The environmental change between low pH in secretory granules and neutral pH in extracellular spaces is believed to drive the reversible fibrillization of β-endorphin. Here, we investigate the critical role of a buried glutamate, Glu8, in the pH-responsive disassembly of β-endorphin fibrils using all-atom molecular dynamics simulations along with structure-based pKa prediction. The fibril was stable at pH 5.5 or lower with all the buried Glu8 residues protonated and neutrally charged. After switching to neutral pH, the Glu8 residues of peptides at the outer layers of the ordered fibrils became deprotonated due to partial solvent exposure, causing sheet-to-coil conformational changes and subsequent exposure of adjacent Glu8 residues in the inner chains. Via iterative deprotonation of Glu8 and induced structural disruption, all Glu8 residues would be progressively deprotonated. Electrostatic repulsion between deprotonated Glu8 residues along with their high solvation tendency disrupted the hydrogen bonding between the β1 strands and increased the solvent exposure of those otherwise buried residues in the cross-β core. Overall, our computational study reveals that the strategic positioning of ionizable residues into the cross-β core is a potential approach for designing reversible amyloid fibrils as pH-responsive smart bio-nanomaterials.

Dataset Information

Cross-α/β polymorphism of PSMα3 fibrils.

Publications

Cross-α/β polymorphism of PSMα3 fibrils.

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