Structures for amyloid fibrils

Makin, O. Sumner; Serpell, Louise C.

doi:10.1111/j.1742-4658.2005.05025.x

Cited by 426 publications

(441 citation statements)

References 105 publications

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“…X-ray fiber diffraction showed that the samples of pure A␤ and mixed ratios all exhibit the classic cross-␤ fiber diffraction patterns described in the literature (38,39), showing a strong meridional reflection at 4.7 Å and a major equatorial reflection at ϳ10 Å consistent with a cross-␤ architecture (Fig. 3B).…”

Section: Direct Interactions Between A␤mentioning

confidence: 61%

Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease

Pauwels

Williams

Morris

et al. 2012

Journal of Biological Chemistry

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Background: Amyloid ␤ peptide plays a role in Alzheimer disease. Results: Interaction of amyloid ␤ peptides with 40 and 42 amino acids has consequences for oligomer formation. Conclusion: Increased production of amyloid ␤ peptide with 42 amino acids affects the behavior of the entire amyloid ␤ peptide pool. Significance: This might explain the synaptotoxic effect observed with a shift in amyloid ␤ peptide production.

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Section: Direct Interactions Between A␤mentioning

confidence: 61%

Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease

Pauwels

Williams

Morris

et al. 2012

Journal of Biological Chemistry

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220

223

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“…In vitro experiments have provided evidence supporting the capability of a large variety of proteins and peptides, including those unrelated to any disease, to self-assemble into amyloid fibrils or amyloid-like structures when incubated under appropriate solution conditions. This has led to the suggestion that the ability to form amyloid fibrils is a fundamental property of polypeptide chains (Glenner et al 1974;Kirschner et al 1987;Maggio and Mantyh 1996;Fändrich and Dobson 2002;Makin and Serpell 2005;Chiti and Dobson 2006;Goldschmidt et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

Sasahara

Goto

2012

Biophys Rev

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The aggregation of proteins into amyloid fibrils is a topic that has attracted great interest because the process is associated with the pathology of numerous human diseases. Despite considerable progress in the elucidation of the structure of amyloid fibrils and the kinetic mechanism of their formation, knowledge on the thermodynamic aspects underlying the formation and stability of amyloid fibrils is limited. In this review, we summarize recent calorimetric studies of amyloid fibril formation, with the goal of obtaining a better understanding of the causal factors that thermally induce proteins to aggregate into amyloid fibrils. Calorimetric data show that differential scanning calorimetry is a useful technique to study the causative factors that thermally trigger the conversion to the amyloid structure and highlight the physics related to the thermal fluctuation of proteins during this conversion.

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“…The best mechanistically characterized examples involve the polymerization of aggregationprone peptides (10,11) or small proteins to give well-defined fibrils based on a regular repeat structure (12)(13)(14)(15)(16)(17)(18). The fibrillar aggregates have a characteristic cross-β X-ray diffraction pattern and bind such dyes as Congo Red and Thioflavine T (ThT) (16). The kinetics of aggregation usually follow a nucleation-growth mechanism, with very slow nucleation (19)(20)(21).…”

mentioning

confidence: 99%

Multisite aggregation of p53 and implications for drug rescue

Wang

Fersht

2017

Proc. Natl. Acad. Sci. U.S.A.

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Protein aggregation is involved in many diseases. Often, a unique aggregation-prone sequence polymerizes to form regular fibrils. Many oncogenic mutants of the tumor suppressor p53 rapidly aggregate but form amorphous fibrils. A peptide surrounding Ile254 is proposed to be the aggregation-driving sequence in cells. We identified several different aggregating sites from limited proteolysis of harvested aggregates and effects of mutations on kinetics and products of aggregation. We present a model whereby the amorphous nature of the aggregates results from multisite branching of polymerization after slow unfolding of the protein, which may be a common feature of aggregation of large proteins. Greatly lowering the aggregation propensity of any one single site, including the site of Ile254, by mutation did not inhibit aggregation in vitro because aggregation could still occur via the other sites. Inhibition of an individual site is, accordingly, potentially unable to prevent aggregation in vivo. However, cancer cells are specifically killed by peptides designed to inhibit the Ile254 sequence and further aggregation-driving sequences that we have found. Consistent with our proposed mechanism of aggregation, we found that such peptides did not inhibit aggregation of mutant p53 in vitro. The cytotoxicity was not eliminated by knockdown of p53 in 2D cancer cell cultures. The peptides caused rapid cell death, much faster than usually expected for p53-mediated transcription-dependent apoptosis. There may also be non-p53 targets for those peptides in cancer cells, such as p63, or the peptides may alter other interactions of partly denatured p53 with receptors.amyloid | mechanism | misfolding | disease T he tumor suppressor p53 is inactivated by mutation in a substantial number of tumors (1-3). Some 30-40% of those oncogenic mutants are simply destabilized by mutations in its core domain. Those mutants are temperature-sensitive, having a WT structure at lower temperatures, but melt at close to body temperature or below and rapidly aggregate (4-6). Protein aggregation occurs in many diseases (7-9). The best mechanistically characterized examples involve the polymerization of aggregationprone peptides (10, 11) or small proteins to give well-defined fibrils based on a regular repeat structure (12-18). The fibrillar aggregates have a characteristic cross-β X-ray diffraction pattern and bind such dyes as Congo Red and Thioflavine T (ThT) (16). The kinetics of aggregation usually follow a nucleation-growth mechanism, with very slow nucleation (19-21). WT p53 itself aggregates at body temperature (4-6, 22-24), and the oncogenic destabilized mutants aggregate even faster to give amorphous structures that display the characteristic diffraction pattern and bind those diagnostic dyes (23, 25), although under certain conditions, such as very high pressure, they will generate regular fibrils (23,26). The mechanism of initiation of aggregation of p53 differs from the usually studied examples. Two molecules of the core domain of p53 exten...

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Structures for amyloid fibrils

Cited by 426 publications

References 105 publications

Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease

Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

Multisite aggregation of p53 and implications for drug rescue

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