Concluding the Amyloid Formation Pathway of a Coiled‐Coil‐Based Peptide from the Size of the Critical Nucleus

Gerling, Ulla I. M.; Miettinen, Markus S.; Koksch, Beate

doi:10.1002/cphc.201402400

Cited by 2 publications

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References 64 publications

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“…Although there are many studies investigating oligomer formation during amyloid growth, [26,35] only a few reports analyzed possible transitions of the secondary structure and oligomer sizes of a peptide at c crit to investigate the influence of supersaturation on biophysical properties of peptides [36] . In most cases c crit is below experimental limits, e. g. in the pM to low μM range for Aβ 40 [24] …”

Section: Introductionmentioning

confidence: 99%

The Prenucleation Equilibrium of the Parathyroid Hormone Determines the Critical Aggregation Concentration and Amyloid Fibril Nucleation

et al. 2023

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Nucleation and growth of amyloid fibrils were found to only occur in supersaturated solutions above a critical concentration (ccrit). The biophysical meaning of ccrit remained mostly obscure, since typical low values of ccrit in the sub‐μM range hamper investigations of potential oligomeric states and their structure. Here, we investigate the parathyroid hormone PTH84 as an example of a functional amyloid fibril forming peptide with a comparably high ccrit of 67±21 μM. We describe a complex concentration dependent prenucleation ensemble of oligomers of different sizes and secondary structure compositions and highlight the occurrence of a trimer and tetramer at ccrit as possible precursors for primary fibril nucleation. Furthermore, the soluble state found in equilibrium with fibrils adopts to the prenucleation state present at ccrit. Our study sheds light onto early events of amyloid formation directly related to the critical concentration and underlines oligomer formation as a key feature of fibril nucleation. Our results contribute to a deeper understanding of the determinants of supersaturated peptide solutions. In the current study we present a biophysical approach to investigate ccrit of amyloid fibril formation of PTH84 in terms of secondary structure, cluster size and residue resolved intermolecular interactions during oligomer formation. Throughout the investigated range of concentrations (1 μM to 500 μM) we found different states of oligomerization with varying ability to contribute to primary fibril nucleation and with a concentration dependent equilibrium. In this context, we identified the previously described ccrit of PTH84 to mark a minimum concentration for the formation of homo‐trimers/tetramers. These investigations allowed us to characterize molecular interactions of various oligomeric states that are further converted into elongation competent fibril nuclei during the lag phase of a functional amyloid forming peptide.

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Section: Introductionmentioning

confidence: 99%

The Prenucleation Equilibrium of the Parathyroid Hormone Determines the Critical Aggregation Concentration and Amyloid Fibril Nucleation

et al. 2023

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Peptide–Protein Interactions: From Drug Design to Supramolecular Biomaterials

2021

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The self-recognition and self-assembly of biomolecules are spontaneous processes that occur in Nature and allow the formation of ordered structures, at the nanoscale or even at the macroscale, under thermodynamic and kinetic equilibrium as a consequence of specific and local interactions. In particular, peptides and peptidomimetics play an elected role, as they may allow a rational approach to elucidate biological mechanisms to develop new drugs, biomaterials, catalysts, or semiconductors. The forces that rule self-recognition and self-assembly processes are weak interactions, such as hydrogen bonding, electrostatic attractions, and van der Waals forces, and they underlie the formation of the secondary structure (e.g., α-helix, β-sheet, polyproline II helix), which plays a key role in all biological processes. Here, we present recent and significant examples whereby design was successfully applied to attain the desired structural motifs toward function. These studies are important to understand the main interactions ruling the biological processes and the onset of many pathologies. The types of secondary structure adopted by peptides during self-assembly have a fundamental importance not only on the type of nano- or macro-structure formed but also on the properties of biomaterials, such as the types of interaction, encapsulation, non-covalent interaction, or covalent interaction, which are ultimately useful for applications in drug delivery.

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Concluding the Amyloid Formation Pathway of a Coiled‐Coil‐Based Peptide from the Size of the Critical Nucleus

Abstract: The size of the critical nucleus acting as intermediate in the amyloid formation of a model peptide is calculated. The theoretical approach is based on experimentally determined amyloid formation rates and gives new insights into the amyloid formation pathway.

Cited by 2 publications

References 64 publications

The Prenucleation Equilibrium of the Parathyroid Hormone Determines the Critical Aggregation Concentration and Amyloid Fibril Nucleation

The Prenucleation Equilibrium of the Parathyroid Hormone Determines the Critical Aggregation Concentration and Amyloid Fibril Nucleation

Peptide–Protein Interactions: From Drug Design to Supramolecular Biomaterials

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