Quantitative approaches for characterising fibrillar protein nanostructures
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Quantitative approaches for characterising fibrillar protein nanostructures Duncan A. Whitea , Christopher M. Dobsona , Mark E Wellandb and Tuomas P. J. Knowlesa a
b
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
Nanoscience Centre, University of Cambridge, J. J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom.
Abstract Polypeptide sequences have an inherent tendency to self-assemble into filamentous nanostructures commonly known as amyloid fibrils. Such self-assembly is used in nature to generate a variety of functional materials ranging from protective coatings in bacteria to catalytic scaffolds in mammals. The aberrant self-assembly of misfolded peptides and proteins is also, however, implicated in a range of disease states including neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases. It is increasingly evident that the intrinsic material properties of these structures are crucial for understanding the thermodynamics and kinetics of the pathological deposition of proteins, particularly as the mechanical fragmentation of aggregates enhances the rate of protein deposition by exposing new fibril ends which can promote further growth. We discuss here recent advances in physical techniques that are able to characterise the hierarchical self-assembly of misfolded protein molecules and define their properties.
Introduction Amyloid fibrils are high aspect ratio protein nanostructures that are formed through the self-assembly of polypeptide chains. They are better known as a result of their association with debilitating disorders such as Alzheimer’s disease and type II diabetes where normally soluble peptide and protein molecules misfold and aggregate into amyloid structures [1, 2]. These highly ordered fibrils are characterised by a ‘cross-β’ core structure formed from β-strands that are predisposed to form fibrillar aggregates and often consist of several protofilaments twisted around one another, resulting in extremely robust mechanical properties [3–5]. Although most natural amyloid structures have pathological associations, in a number of cases they may be found to have biologically functional roles [6, 7]. As a result of this situation, a detailed and quantitative characterisation of the material properties and growth kinetics of amyloid fibrils is essential to the development of novel and responsive multidimensional templates and biomaterials for future technological applications [8–13]. Such an approach aimed at bridging the nano and macro scales necessitates discussion of appropriate quantitative methods to probe the material properties of amyloid fibrils and the kinetics of their assembly.
In addition to material considerations, it is critically important to obtain quantitative measurements of fibril growth and breakage as these are key factors related to the proliferation of amyloid structure in many debilitating diseases [14–17]. This article therefore focuses on these two aspects of amyloid systems and demons
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