Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state

Gefei Chen, Axel Abelein, Harriet E. Nilsson, Axel Leppert, Yuniesky Andrade-Talavera, Simone Tambaro, Lovisa Hemmingsson, Firoz Roshan, Michael Landreh, Henrik Biverstål, Philip J. B. Koeck, Jenny Presto, Hans Hebert, André Fisahn and Jan Johansson ()
Additional contact information
Gefei Chen: Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet
Axel Abelein: Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet
Harriet E. Nilsson: Karolinska Institutet, and School of Technology and Health, KTH Royal institute of Technology
Axel Leppert: Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet
Yuniesky Andrade-Talavera: Care Sciences and Society, Center for Alzheimer Research, Neuronal Oscillations Lab, Karolinska Institutet
Simone Tambaro: Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet
Lovisa Hemmingsson: Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet
Firoz Roshan: Care Sciences and Society, Center for Alzheimer Research, Neuronal Oscillations Lab, Karolinska Institutet
Michael Landreh: University of Oxford, South Parks Road
Henrik Biverstål: Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet
Philip J. B. Koeck: Karolinska Institutet, and School of Technology and Health, KTH Royal institute of Technology
Jenny Presto: Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet
Hans Hebert: Karolinska Institutet, and School of Technology and Health, KTH Royal institute of Technology
André Fisahn: Care Sciences and Society, Center for Alzheimer Research, Neuronal Oscillations Lab, Karolinska Institutet
Jan Johansson: Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer’s disease the amyloid-β peptide (Aβ) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces Aβ fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible non-fibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of Aβ, while dimers strongly suppress Aβ fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. These results indicate that Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity.

Date: 2017
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DOI: 10.1038/s41467-017-02056-4

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