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Nat Commun. 2016 Mar 24;7:10948. doi: 10.1038/ncomms10948.

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

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Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Department of Biochemistry and Structural Biology, Lund University, Box 124, SE221 00 Lund, Sweden.
Center for Alzheimer Research, Division for Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, S-141 57 Huddinge, Sweden.


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.

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