Structural Elements Regulating Interactions in the Early Stages of Fibrillogenesis: A Human Calcitonin Model System

Vitale, Rosa Maria; Andreotti, Giuseppina; Amodeo, Pietro; Motta, Andréa

doi:10.1002/9781118183373.ch12

Cited by 2 publications

(1 citation statement)

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“…Intrinsically disordered segments of otherwise folded proteins are involved in pivotal protein–DNA and ligand–receptor interactions [ 5 , 8 ]. Some IDPs are of great biomedical relevance in that they are prone to self-assembly into amyloid fibrils [ 9 , 10 , 11 ]. Canonical examples are the amyloid β-peptides Aβ 1-40 and Aβ 1-42 , α-synuclein and the tau protein [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring Nearest Neighbor Interactions and Their Influence on the Gibbs Energy Landscape of Unfolded Proteins and Peptides

Schweitzer‐Stenner

2022

IJMS

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The Flory isolated pair hypothesis (IPH) is one of the corner stones of the random coil model, which is generally invoked to describe the conformational dynamics of unfolded and intrinsically disordered proteins (IDPs). It stipulates, that individual residues sample the entire sterically allowed space of the Ramachandran plot without exhibiting any correlations with the conformational dynamics of its neighbors. However, multiple lines of computational, bioinformatic and experimental evidence suggest that nearest neighbors have a significant influence on the conformational sampling of amino acid residues. This implies that the conformational entropy of unfolded polypeptides and proteins is much less than one would expect based on the Ramachandran plots of individual residues. A further implication is that the Gibbs energies of residues in unfolded proteins or polypeptides are not additive. This review provides an overview of what is currently known and what has yet to be explored regarding nearest neighbor interactions in unfolded proteins.

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Section: Introductionmentioning

confidence: 99%

Exploring Nearest Neighbor Interactions and Their Influence on the Gibbs Energy Landscape of Unfolded Proteins and Peptides

Schweitzer‐Stenner

2022

IJMS

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A dimer model of human calcitonin13-32 forms an α-helical structure and robustly aggregates in 50% aqueous 2,2,2-trifluoroethanol solution

et al. 2016

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Determining the cause of human calcitonin (hCT) aggregation could be of help in the effort to utilize hCT for treatment of hypercalcemia. Here we report that a dimer model of hCT13-32 aggregated to a greater degree than native hCT under aqueous 2,2,2-trifluoroethanol conditions. Analyses using circular dichroism spectroscopy, thioflavine-T binding assays and atomic force microscopy suggest that the α-helical portion of hCT is important for initiation of the aggregation process, which yields long fibrils. Dimerization, which stabilizes the β-sheet structure of hCT, enhances aggregation potency. Dimerization of hCT stabilizes the α-helix under aqueous TFE conditions, leading to the long fibril formation. Up to now, there have been no reports of using a dimer model to investigate the properties of hCT aggregation. Our findings could potentially serve as the basis for development of novel hCT derivatives that could be utilized for treatment of hypercalcemia, as well as for development of novel therapeutics for other ailments caused by amyloid peptides. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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Structural Elements Regulating Interactions in the Early Stages of Fibrillogenesis: A Human Calcitonin Model System

Cited by 2 publications

References 154 publications

Exploring Nearest Neighbor Interactions and Their Influence on the Gibbs Energy Landscape of Unfolded Proteins and Peptides

Exploring Nearest Neighbor Interactions and Their Influence on the Gibbs Energy Landscape of Unfolded Proteins and Peptides

A dimer model of human calcitonin13-32 forms an α-helical structure and robustly aggregates in 50% aqueous 2,2,2-trifluoroethanol solution

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