Role of Intermolecular Forces in Defining Material Properties of Protein Nanofibrils

Knowles, Tuomas P. J.; Fitzpatrick, Anthony; Meehan, Sarah; Mott, Helen R.; Vendruscolo, Michele; Welland, Mark E.

doi:10.1126/science.1150057

Cited by 705 publications

(889 citation statements)

References 27 publications

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“…Three peaks represent the relative stiffness of (i) spherical oligomers and nanofibrils (3.2 ± 1.1 GPa), (ii) a newfound peptide molecular monolayer (9.6 ± 0.6 GPa), and (iii) graphite (24.0 ± 2.8 GPa), respectively. The stiffness of the amyloid fibrils determined is consistent with the ones in the previous researches 24. The newfound molecular monolayer structure is three times stiffer than conventional amyloid fibrils and spherical oligomers.…”

Section: Resultssupporting

confidence: 89%

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Liu

Zhang

et al. 2016

Advanced Science

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The differentiation of protein properties and biological functions arises from the variation in the primary and secondary structure. Specifically, in abnormal assemblies of protein, such as amyloid peptide, the secondary structure is closely correlated with the stable ensemble and the cytotoxicity. In this work, the early Aβ33‐42 aggregates forming the molecular monolayer at hydrophobic interface are investigated. The molecular monolayer of amyloid peptide Aβ33‐42 consisting of novel parallel β‐strand‐like structure is further revealed by means of a quantitative nanomechanical spectroscopy technique with force controlled in pico‐Newton range, combining with molecular dynamic simulation. The identified parallel β‐strand‐like structure of molecular monolayer is distinct from the antiparallel β‐strand structure of Aβ33‐42 amyloid fibril. This finding enriches the molecular structures of amyloid peptide aggregation, which could be closely related to the pathogenesis of amyloid disease.

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Section: Resultssupporting

confidence: 89%

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Liu

Zhang

et al. 2016

Advanced Science

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“…[35][36][37][38] (2) New ideas about protein aggregation, 10,28 including the finding that the ability to assemble into stable and highly organised structures (e.g. amyloid fibrils) is not an unusual feature exhibited by a small group of peptides and proteins with special sequence or structural properties, but rather a property shared by most, if not all, proteins; (3) The discovery that specific aspects of protein behaviour, including their aggregation propensities 21,23,39,40 and the cellular toxicity associated with the aggregation process, 24,41 can be predicted with a remarkable degree of accuracy from the knowledge of their amino acid sequences; (4) The realisation that a wide variety of techniques originally devised for applications in nanotechnology can be used to probe the nature of protein aggregation and assembly and of the structures that emerge; 30,[42][43][44] and (5) The development of powerful approaches using model organisms for probing the origins and progression of misfolding diseases by linking concepts and principles emerging from in vitro studies to in vivo phenomena such as neurodegeneration. 24 An analysis of these results, which span across a wide range of subjects from neuroscience to nanoscience, reveals that the ability to keep proteins in their soluble form is absolutely central for the maintenance of cell homeostasis.…”

Section: A Conceptual Framework For Understanding Protein Homeostasismentioning

confidence: 99%

“…Powerful techniques are being developed to complement more established methods to overcome the challenges posed by the task of providing such a description. 30,[42][43][44]46 Our own approach is based primarily on methods that directly combine experimental and computational techniques. 5,6,35 These procedures involve the use of experimental data, largely derived from NMR spectroscopy, as restraints in computer simulations.…”

Section: Multiple Forms Of Protein Structurementioning

confidence: 99%

“…[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. This work reveals that hydrogen bonded arrays of polypeptide chains exhibit material properties intermediate between those of hard materials such as steel and carbon nanotubes and softer biological fibres such as tubulin and actin (Fig.…”

Section: Molecular Basis Of Protein Aggregationmentioning

confidence: 99%

“…Because the structural interactions within the amyloid state and the native state are similar-although the latter are largely intramolecular whilst the former also include strong intermolecular contributions-the stability of the native and amyloid states can be comparable. 30 There is thus a competition between the two states that results in normal or aberrant biological behaviour depending on whether the native or the aggregated state is populated. 10,28,29 More generally, the maintenance of the correct balance in the populations of different states of proteins, one facet of protein homeostasis, is of great significance, as even marginal alterations in such populations can result in disease in the long term.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative approaches to defining normal and aberrant protein homeostasis

Vendruscolo

2009

Faraday Discuss.

Self Cite

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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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Alpha‐Synuclein

Cremades

2017

Encyclopedia of Life Sciences

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α‐Synuclein (αS) is a presynaptic small protein that has attracted much interest because its aggregation and accumulation in the form of amyloid fibrils is the hallmark of a range of neurodegenerative disorders, collectively referred to as synucleinopathies. Despite intense research on this protein since it was first identified two decades ago as the major component of the proteinaceous intracellular inclusion characteristics of Parkinson disease, there is still no consensus on the physiological function of the protein and much remains to be established on the molecular basis of its toxicity. Recently, important steps have been undertaken to identify the different conformational states that this protein is able to adopt and elucidate their role in physiological and pathological conditions. Key Concepts The physiological function(s) of α‐synuclein remains controversial, although recent evidences suggest a major regulatory role in synapsis. At physiological conditions, α‐synuclein is in a dynamic equilibrium between a membrane‐bound α‐helical (likely multimeric) conformation and a cytosolic intrinsically disordered (monomeric) conformation. α‐Synuclein aggregation and fibril formation likely play a central role in Parkinson disease and other neurodegenerative disorders. Different strains or fibril polymorphs of α‐synuclein have different degrees of infectivity and might be associated with distinct types of pathologies. Different mechanisms of formation of α‐synuclein amyloid aggregates have been observed in vitro , but their relative relevance in vivo remains unknown. Recent studies support the idea that multiple aggregated species of α‐synuclein can be generated through diverse misfolding pathways during the process of amyloid aggregation and could play distinct roles during the development of disease. Combined methods to target specifically different α‐synuclein conformations could potentially prevent α‐synuclein‐associated toxicity.

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Role of Intermolecular Forces in Defining Material Properties of Protein Nanofibrils

Cited by 705 publications

References 27 publications

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Quantitative approaches to defining normal and aberrant protein homeostasis

Alpha‐Synuclein

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