Lysozyme Amyloidogenesis Is Accelerated by Specific Nicking and Fragmentation but Decelerated by Intact Protein Binding and Conversion

Mishra, Rajesh; Sörgjerd, Karin; Nyström, Sofie; Nordigården, Amanda; Yu, Yen-Chi; Hammarström, Per

doi:10.1016/j.jmb.2006.11.084

Cited by 187 publications

(222 citation statements)

References 44 publications

(66 reference statements)

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“…The latter proposed to be specific to hydrophobic regions. There are reports that Nile Red binds to both nonspecific aggregates and amyloid fibrils (43,44). Under acidic conditions with 10% (v/v) HFIP, the ThT florescence and Nile Red fluorescence overlapped (Fig.…”

Section: Formation Of Fibrils Under Acidicmentioning

confidence: 87%

Hexafluoroisopropanol Induces Amyloid Fibrils of Islet Amyloid Polypeptide by Enhancing Both Hydrophobic and Electrostatic Interactions

Yanagi

Ashizaki

Yagi

et al. 2011

Journal of Biological Chemistry

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Although amyloid fibrils deposit with various proteins, the comprehensive mechanism by which they form remains unclear. We studied the formation of fibrils of human islet amyloid polypeptide associated with type II diabetes in the presence of various concentrations of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) under acidic and neutral pH conditions using CD, amyloid-specific thioflavin T fluorescence, fluorescence imaging with thioflavin T, and atomic force microscopy. At low pH, the formation of fibrils was promoted by HFIP with an optimum at 5% (v/v). At neutral pH in the absence of HFIP, significant amounts of amorphous aggregates formed in addition to the fibrils. The addition of HFIP suppressed the formation of amorphous aggregates, leading to a predominance of fibrils with an optimum effect at 25% (v/v). Under both conditions, higher concentrations of HFIP dissolved the fibrils and stabilized the ␣-helical structure. The results indicate that fibrils and amorphous aggregates are different types of precipitates formed by exclusion from water-HFIP mixtures. The exclusion occurs through the combined effects of hydrophobic interactions and electrostatic interactions, both of which are strengthened by low concentrations of HFIP, and a subtle balance between the two types of interactions determines whether the fibrils or amorphous aggregates dominate. We suggest a general view of how the structure of precipitates varies dramatically from single crystals to amyloid fibrils and amorphous aggregates.

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Section: Formation Of Fibrils Under Acidicmentioning

confidence: 87%

Hexafluoroisopropanol Induces Amyloid Fibrils of Islet Amyloid Polypeptide by Enhancing Both Hydrophobic and Electrostatic Interactions

Yanagi

Ashizaki

Yagi

et al. 2011

Journal of Biological Chemistry

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“…For fibril growth at pH 1.6 and 65 • C, lysozyme hydrolysis was shown to accelerate fibril formation. 24 Exposure of mature fibril to acid pH during extended incubations caused portions of the native structure to be trimmed off the fibrils. 23 We, therefore, investigated whether the existence of the oligomer-free vs. oligomeric pathway, or the specific features of their FTIR spectra shown here, were affected by lysozyme hydrolysis.…”

Section: Pathway-specific Structural Features Are Independent Of Growmentioning

confidence: 99%

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

Foley

Hill

Miti

et al. 2013

The Journal of Chemical Physics

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Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathwayspecific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the entire cascade of aggregation intermediates formed along each pathway. © 2013 AIP Publishing LLC. [http://dx

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“…In the case of lysozyme aggregation under harsh denaturating conditions, the process becomes nearly concentration-independent (␥ Ӎ 0) for protein concentrations significantly higher than the solubility (40). The formation of intermediate and off-pathway species is a likely explanation of this and of other deviations from canonical kinetics, as illustrated next for HEWL aggregation under conditions of low pH (1.6) and high temperature (60°C) known to produce aggregates other than amyloid fibrils (44,45,46).…”

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confidence: 91%

What Can the Kinetics of Amyloid Fibril Formation Tell about Off-pathway Aggregation?

Crespo

Villar‐Alvarez

Taboada

et al. 2016

Journal of Biological Chemistry

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Some of the most prevalent neurodegenerative diseases are characterized by the accumulation of amyloid fibrils in organs and tissues. Although the pathogenic role of these fibrils has not been completely established, increasing evidence suggests offpathway aggregation as a source of toxic/detoxicating deposits that still remains to be targeted. The present work is a step toward the development of off-pathway modulators using the same amyloid-specific dyes as those conventionally employed to screen amyloid inhibitors. We identified a series of kinetic signatures revealing the quantitative importance of off-pathway aggregation relative to amyloid fibrillization; these include nonlinear semilog plots of amyloid progress curves, highly variable end point signals, and half-life coordinates weakly influenced by concentration. Molecules that attenuate/intensify the magnitude of these signals are considered promising off-pathway inhibitors/promoters. An illustrative example shows that amyloid deposits of lysozyme are only the tip of an iceberg hiding a crowd of insoluble aggregates. Thoroughly validated using advanced microscopy techniques and complementary measurements of dynamic light scattering, CD, and soluble protein depletion, the new analytical tools are compatible with the high-throughput methods currently employed in drug discovery.

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Lysozyme Amyloidogenesis Is Accelerated by Specific Nicking and Fragmentation but Decelerated by Intact Protein Binding and Conversion

Cited by 187 publications

References 44 publications

Hexafluoroisopropanol Induces Amyloid Fibrils of Islet Amyloid Polypeptide by Enhancing Both Hydrophobic and Electrostatic Interactions

Hexafluoroisopropanol Induces Amyloid Fibrils of Islet Amyloid Polypeptide by Enhancing Both Hydrophobic and Electrostatic Interactions

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

What Can the Kinetics of Amyloid Fibril Formation Tell about Off-pathway Aggregation?

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