Journal ArticleDOI
The thermodynamic stability of amyloid fibrils studied by differential scanning calorimetry.
TLDR
This work analyzed the thermal melting of the amyloid fibrils of the N47A mutant of the alpha-spectrin SH3 domain by differential scanning calorimetry (DSC) and found that with the use of appropriate models of analysis DSC has an extraordinary potential to analyze the thermodynamic determinants of amyloids fibril stability.Abstract:
In contrast to the thermal unfolding of native proteins, very few studies of the thermally induced melting of amyloid fibrils have been reported to date due to the complex nature of these protein aggregates and the lack of theoretical formalisms to rationalize the data. In this work, we analyzed the thermal melting of the amyloid fibrils of the N47A mutant of the alpha-spectrin SH3 domain by differential scanning calorimetry (DSC). The thermal melting of the isolated fibrils occurred in single endothermic transitions, yielding the fully unfolded protein. The enthalpy and heat capacity changes of fibril melting were significantly lower than those of the unfolding of the native protein, indicating a lower density of interactions and a higher solvent-exposed surface area for the protein within the fibrils relative to the native state. In addition, these magnitudes did not change significantly between fibrils showing different morphology. The independence of the transitions with the scan rate and the observation of a considerable mass-action-like effect upon the melting temperatures indicated that the fibril melting is not separated significantly from equilibrium and could be considered in good approximation as a reversible process. A simple equilibrium model of polymerization coupled to monomer unfolding allowed us for the first time to interpret quantitatively the thermal melting of amyloid fibrils. The model captured very well the general features of the thermal behavior of amyloid fibrils and allowed us to estimate the partitioning of the energy of overall melting into the unfolding of monomers and fibril elongation. We conclude that with the use of appropriate models of analysis DSC has an extraordinary potential to analyze the thermodynamic determinants of amyloid fibril stability.read more
Citations
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Journal ArticleDOI
Differential scanning calorimetry as a tool for protein folding and stability.
TL;DR: The potential uses of DSC in studying protein folding and stability are described, giving brief examples of applications from the recent literature.
Journal ArticleDOI
Multicomponent peptide assemblies
TL;DR: The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.
Journal ArticleDOI
Inhibiting, promoting, and preserving stability of functional protein fibrils
Owen G. Jones,Raffaele Mezzenga +1 more
TL;DR: While various strategies are presented on the breakdown of mature protein fibrils, emphasis is given to the approaches leading to increased rigidity and length of resultant fibril.
Journal ArticleDOI
Liquid-Liquid Phase Separation and Its Mechanistic Role in Pathological Protein Aggregation.
TL;DR: This review aims to assess the molecular basis of this link between LLPS and aggregation and the underlying mechanisms facilitating maturation of liquid droplets into more stable assemblies, including so-called labile fibrils, hydrogels, and pathological amyloids.
Journal ArticleDOI
Environmental Conditions Affect the Kinetics of Nucleation of Amyloid Fibrils and Determine Their Morphology
TL;DR: The results suggest that the influence of environmental variables on protein solvation is crucial in determining the nucleation kinetics, the pathway of assembly, and the final fibril morphology.
References
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Journal ArticleDOI
Protein Misfolding, Functional Amyloid, and Human Disease
TL;DR: The relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate is discussed and some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior is described.
Book ChapterDOI
Stability of Proteins Small Globular Proteins
TL;DR: The chapter discusses the stability of proteins and presents the results obtained on small compact globular proteins, which represent one single cooperative system, and the temperature-induced changes in protein, denaturational and predenaturational changes inprotein, thermodynamics of protein unfolding, and thermodynamic properties of protein.
Journal ArticleDOI
Structure of the cross-beta spine of amyloid-like fibrils.
Rebecca Nelson,Michael R. Sawaya,Melinda Balbirnie,Anders Ø. Madsen,Anders Ø. Madsen,Christian Riekel,Robert Grothe,David Eisenberg +7 more
TL;DR: The atomic structure of the cross-β spine illuminates the stability of amyloid fibrils, their self-seeding characteristic and their tendency to form polymorphic structures.
Journal ArticleDOI
MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid Proteins
James Harper,Peter T. Lansbury +1 more
TL;DR: A simple mechanistic model has emerged for both processes that involves a nucleation-dependent polymerization that dictates that aggregation is dependent on protein concentration and time.
Journal ArticleDOI
Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution
TL;DR: The 'new view' of these diseases suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses, and suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.