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

Paolo Arosio, Thomas C. T. Michaels, Sara Linse, Cecilia Månsson, Cecilia Emanuelsson, Jenny Presto, Jan Johansson, Michele Vendruscolo (), Christopher M. Dobson () and Tuomas P. J. Knowles ()
Additional contact information
Paolo Arosio: University of Cambridge
Thomas C. T. Michaels: University of Cambridge
Sara Linse: Lund University
Cecilia Månsson: Lund University
Cecilia Emanuelsson: Lund University
Jenny Presto: Center for Alzheimer Research, Care Sciences and Society, Karolinska Institutet
Jan Johansson: Center for Alzheimer Research, Care Sciences and Society, Karolinska Institutet
Michele Vendruscolo: University of Cambridge
Christopher M. Dobson: University of Cambridge
Tuomas P. J. Knowles: University of Cambridge

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10948

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