Amyloid Fibrils of the HET-s(218–289) Prion Form a β Solenoid with a Triangular Hydrophobic Core

Wasmer, Christian; Lange, Adam; Melckebeke, Hélène Van; Siemer, Ansgar B.; Riek, Roland; Meier, Beat H.

doi:10.1126/science.1151839

Cited by 943 publications

(1,187 citation statements)

References 37 publications

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“…69 In addition to information about the structure of the amyloid fibrils formed by an 11-residue fragment of human transthyretin, these approaches have provided great insight into the structures of amyloid fibrils formed by several other peptides and proteins, including Het-S and Ab. [70][71][72] Together with the strategy mentioned above, nanoscience techniques are also emerging as powerful tools that can provide insight into the factors that stabilise amyloid fibrils. 30,42,44 In an initial study, by using atomic force microscopy (AFM) imaging we described the changes in the distribution of inter-versus intra-molecular bonding interactions associated with the transition of proteins from their native globular structures into ordered supramolecular assemblies.…”

Section: Molecular Basis Of Protein Aggregationmentioning

confidence: 99%

Quantitative approaches to defining normal and aberrant protein homeostasis

Vendruscolo

2009

Faraday Discuss.

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Protein homeostasis refers to the ability of cells to generate and regulate the levels of their constituent proteins in terms of conformations, interactions, concentrations and cellular localisation. We discuss here an approach in which physico-chemical properties of proteins and their environments are used to understand the underlying principles governing this process, which is crucial in all living systems. By adopting the strategy of characterising the origins of specific diseases to inform us about normal biology, we are bringing together methods and concepts from chemistry, physics, engineering, genetics and medicine. In particular, we are using a combination of in vitro, in silico and in vivo approaches to study protein homeostasis through the analysis of the effects that result from its perturbation in a select group of specific proteins, from either amino acid mutations, or changes in concentration and solubility, or interactions with other molecules. By developing a coherent and quantitative description of such phenomena, we are finding that it is possible to shed new light on how the physical and chemical properties of the cellular components can provide an understanding of the normal and aberrant behaviour of living systems. Through such an approach it is possible to provide new insights into the origin and consequences of the failure to maintain homeostasis that is associated with neurodegenerative diseases, in particular, and the phenomenon of ageing, in general, and hence provide a framework for the rational design of therapeutic approaches.

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Section: Molecular Basis Of Protein Aggregationmentioning

confidence: 99%

Quantitative approaches to defining normal and aberrant protein homeostasis

Vendruscolo

2009

Faraday Discuss.

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“…[22][23][24] This suggests a subtle competition between the specificity of the side chains and the periodicity of the backbone H-bonds. This paper posits that the nearly crystalline state is achieved by an exhaustive search of the potential alignments.…”

Section: Introductionmentioning

confidence: 99%

Kinetic theory of amyloid fibril templating

Schmit

2013

The Journal of Chemical Physics

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The growth of amyloid fibrils requires a disordered or partially unfolded protein to bind to the fibril and adapt the same conformation and alignment established by the fibril template. Since the H-bonds stabilizing the fibril are interchangeable, it is inevitable that H-bonds form between incorrect pairs of amino acids which are either incorporated into the fibril as defects or must be broken before the correct alignment can be found. This process is modeled by mapping the formation and breakage of H-bonds to a one-dimensional random walk. The resulting microscopic model of fibril growth is governed by two timescales: the diffusion time of the monomeric proteins, and the time required for incorrectly bound proteins to unbind from the fibril. The theory predicts that the Arrhenius behavior observed in experiments is due to off-pathway states rather than an on-pathway transition state. The predicted growth rates are in qualitative agreement with experiments on insulin fibril growth rates as a function of protein concentration, denaturant concentration, and temperature. These results suggest a templating mechanism where steric clashes due to a single mis-aligned molecule prevent the binding of additional molecules.

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“…Strukturanalyse mittels Magnetresonanz-("nuclear magnetic resonance", NMR-) Spektroskopie erfordert eine kostspielige und aufwendige Markierung großer Proteinmengen mit Isotopen wie 15 [9,26]). …”

Section: Strukturanalyse Mittels Magnetresonanzspektroskopieunclassified

Struktur von Amyloidfibrillen

Meinhardt

Fändrich

2009

Pathologe

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Amyloid Fibrils of the HET-s(218–289) Prion Form a β Solenoid with a Triangular Hydrophobic Core

Cited by 943 publications

References 37 publications

Quantitative approaches to defining normal and aberrant protein homeostasis

Quantitative approaches to defining normal and aberrant protein homeostasis

Kinetic theory of amyloid fibril templating

Struktur von Amyloidfibrillen

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