Why Proteins Misfold

Campioni, Silvia; Monsellier, Élodie; Chiti, Fabrizio

doi:10.1002/9780470572702.ch1

Cited by 4 publications

(4 citation statements)

References 117 publications

(82 reference statements)

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“…The aggregation of soluble peptides and proteins into amyloid fibrils is the hallmark of more than 50 human disorders, including severe neurodegenerative pathologies. − Considerable effort was therefore spent in the last decades to elucidate the structure of the fibrils, their mechanism of formation, , and the factors influencing such aggregation processes . Amyloid fibrils are generally formed through nucleation-dependent polymerization, which is characterized by a lag-phase (attributed at the microscopic level to the energetically unfavorable nucleation step) followed by rapid growth and elongation of the nuclei, or seeds, into fibrils and a final stationary phase that reflects the equilibrium between fibrils and monomers. ,, Aggregation kinetics are often monitored by means of thioflavin T (ThT) binding measurements, a dye that specifically recognizes the cross-β structure typical of amyloid fibrils. , The factors so far considered to determine the aggregation behavior in vitro of proteins/peptides are mainly their intrinsic (sequence-based) propensity to aggregate, , the sample conditions (concentration, pH, presence of cosolvents, ionic strength), , and the incubation conditions (temperature, volume of sample, presence/absence of shaking). − …”

Section: Introductionmentioning

confidence: 99%

The Presence of an Air–Water Interface Affects Formation and Elongation of α-Synuclein Fibrils

Campioni¹,

Carret

Jördens³

et al. 2014

J. Am. Chem. Soc.

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The aggregation of human α-Synuclein (α-Syn) into amyloid fibrils is related to the onset of multiple diseases termed synucleinopathies. Substantial evidence suggests that hydrophobic-hydrophilic interfaces promote the aggregation of amyloidogenic proteins and peptides in vitro. In this work the effect of the air-water interface (AWI) on α-Syn aggregation is investigated by means of thioflavin T binding measurements, dynamic light scattering, size-exclusion chromatography, electron microscopy, and atomic force microscopy. Measurements were performed with the monomeric protein alone or together with preformed seeds. In presence of the AWI, α-Syn aggregates readily into amyloid fibrils that remain adsorbed to the AWI. Instead, when the AWI is removed from the samples by replacing it with a solid-liquid interface, the interfacial aggregation of monomeric α-Syn is greatly reduced and no significant increase in ThT fluorescence is detected in the bulk, even at 900 μM concentration. Bulk aggregation is observed only when a sufficient amount of preformed seeds is added, and the initial slope of the kinetics scales with the amount of seeds as expected for first order kinetics. By contrast, in seeded experiments with the AWI, the initial slope is one order of magnitude lower and secondary nucleation pathways appear instead to be dominant. Thus, interfaces play multiple roles in the aggregation of α-Syn, influencing primary nucleation, aggregate elongation, and secondary nucleation processes. Interfacial effects must therefore be taken into account to achieve a complete understanding of protein aggregation events in vitro as well as in vivo.

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Section: Introductionmentioning

confidence: 99%

The Presence of an Air–Water Interface Affects Formation and Elongation of α-Synuclein Fibrils

Campioni¹,

Carret

Jördens³

et al. 2014

J. Am. Chem. Soc.

Self Cite

250

234

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“…On the other hand, the β-sheet increase is due to keratin misfolding in amyloid-like fibrilsintermolecular β-sheets involved in protein aggregation (Campioni et al, 2010;Balzani et al,2012). We can conclude that the damage produced by psoriasis in fingernails is associated with the α-β transition followed by a β-sheet-mediated protein aggregation.…”

Section: To the Editormentioning

confidence: 99%

Degradation Mechanism Induced by Psoriasis in Human Fingernails: A Different Approach

Coroabă

Pinteala

Chiriac

et al. 2016

Journal of Investigative Dermatology

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“…Much fewer are the studies that use rate equations accounting for the possibility for the monomers to be in conformational state (e.g., natively folded) that prevents them from assembling into fibrils and thus renders them fibrillation-passive. Transformation of the protein monomers from fibrillation-passive into fibrillation-active ones (called hereafter P monomers and A monomers, respectively) occurs for various reasons (see, e.g., ref ). This transformation may be an important prefibrillation step for solutions populated by P-monomers ,,,− and an essential determinant in the fibril elongation rate .…”

Section: Introductionmentioning

confidence: 99%

Modeling the Effect of Monomer Conformational Change on the Early Stage of Protein Self-Assembly into Fibrils

Kashchiev

2016

J. Phys. Chem. B

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Filamentous self-assembly of proteins is an important process implicated in a plethora of human diseases and of interest for nanotechnology. Using rate equations, we analyze the early stage of the process in solutions that initially contain fibrillation-passive protein monomers and in which the nascent fibrils are practically insoluble. The analysis is based on a model accounting for the conformational and/or other changes the passive monomers experience to transform themselves into fibrillation-active monomers and thus become fibril nuclei. The model allows exact, comprehensive, and simple mathematical description of the early stage of fibrillation, which reveals the usually neglected role of the nucleation nonstationarity in this stage of fibrillation. We obtain exact and user-friendly expressions for experimentally accessible quantities such as the size distribution of fibrils, their number and mass concentrations, the rate and nonstationary period of fibril nucleation, and the delay time of fibril formation. Analyzing available experimental data, we find that the theory successfully describes the fibrillation time course of pathological and nonpathological ataxin-3, a protein involved in the neurodegenerative disorder spinocerebellar ataxia type-3. The analysis provides mechanistic insight into the reason for the higher fibril nucleation and elongation rates of the pathological ataxin-3.

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Why Proteins Misfold

Cited by 4 publications

References 117 publications

The Presence of an Air–Water Interface Affects Formation and Elongation of α-Synuclein Fibrils

The Presence of an Air–Water Interface Affects Formation and Elongation of α-Synuclein Fibrils

Degradation Mechanism Induced by Psoriasis in Human Fingernails: A Different Approach

Modeling the Effect of Monomer Conformational Change on the Early Stage of Protein Self-Assembly into Fibrils

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