Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation.

Paolo Arosio,Jan Johansson,Cecilia Emanuelsson,Tuomas P J Knowles,Christopher M Dobson,Sara Linse,Michele Vendruscolo,Cecilia Månsson,Thomas C T Michaels,Jenny Presto

doi:10.1038/ncomms10948

Paolo Arosio, Jan Johansson + Show 8 more

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https://doi.org/10.1038/ncomms10948

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Abstract

It is increasingly recognized that molecular chaperones play a key role in modulating the formation of amyloid fibrils, a process associated with a wide range of human disorders. Understanding the detailed mechanisms by which they perform this function, however, has been challenging because of the great complexity of the protein aggregation process itself. In this work, we build on a previous kinetic approach and develop a model that considers pairwise interactions between molecular chaperones and different protein species to identify the protein components targeted by the chaperones and the corresponding microscopic reaction steps that are inhibited. We show that these interactions conserve the topology of the unperturbed reaction network but modify the connectivity weights between the different microscopic steps. Moreover, by analysing several protein-molecular chaperone systems, we reveal the striking diversity in the microscopic mechanisms by which molecular chaperones act to suppress amyloid formation.

Highlights

It is increasingly recognized that molecular chaperones play a key role in modulating the formation of amyloid fibrils, a process associated with a wide range of human disorders
In the presence of a molecular chaperone, the kinetics of aggregation may be altered as a result of the interactions between the molecular chaperone and one or more of the protein species present in the system, which can lead to fundamental changes in the microscopic events involved in the aggregation process
The comparison between the sets of kinetic rate constants defined in the absence and presence of different concentrations of each molecular chaperone provides quantitative information on the microscopic processes that are affected by its presence

Summary

Introduction

It is increasingly recognized that molecular chaperones play a key role in modulating the formation of amyloid fibrils, a process associated with a wide range of human disorders. In the context of the malignant growth of tumours, enzymes involved in cell signalling, kinases, are widely investigated as targets for intervention and for the design of drug discovery programmes Another intriguing example of dysfunctional cellular behaviour involves the pathogenic aggregation of normally soluble peptides and proteins into aberrant insoluble species known as amyloid fibrils[1]. Molecular chaperones are vital components of the protein quality control system, which assist in the synthesis, folding, trafficking and degradation of proteins[6,7,8] In addition to these roles, increasing evidence from in vitro and in vivo studies in the last decade have demonstrated that molecular chaperones play important roles in the specific suppression of amyloid formation and of the toxicity that is associated with this process[8,9,10,11,12,13,14,15]. Elongation Primary and secondary nucleation Elongation Secondary nucleation nonlinear nature of the protein aggregation kinetics; the latter arises from the fact that the kinetics are the result of a combination of a range of microscopic reactions involving primary and secondary nucleation, fibril growth and other secondary phenomena such as fibril fragmentation[19,20,21,22,23,24,25]

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