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Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Karolinska Institute, Sweden; KTH Royal Institute Technology, Sweden.
Karolinska Institute, Sweden.
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 2081Article in journal (Refereed) Published
Abstract [en]

. Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimers disease the amyloid-beta peptide (A beta) 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 A beta fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible nonfibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of A beta, while dimers strongly suppress A beta 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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 8, article id 2081
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-143905DOI: 10.1038/s41467-017-02056-4ISI: 000417702300032PubMedID: 29234026OAI: oai:DiVA.org:liu-143905DiVA, id: diva2:1170047
Note

Funding Agencies|KID PhD studentship grant (FRK); Swedish Research Council; Center for Innovative Medicine (CIMED); Swedish Alzheimer foundation; Swedish Brain Foundation; Karolinska Institutet; Stiftelsen fur Gamla Tjanarinnor; Instruct RD pilot project [APPID 272]; Loo and Hans Osterman Foundation; Geriatric Diseases Foundation at Karolinska Institutet; VIAA Latvia [NFI/R/2014/023]; Latvian Institute of Organic Synthesis

Available from: 2018-01-02 Created: 2018-01-02 Last updated: 2018-01-26

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