Oligomerization of a molecular chaperone modulates its activity

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Abstract

Molecular chaperones alter the folding properties of cellular proteins via mechanisms that are not well understood. Here we show that Trigger Factor (TF), an ATP-independent chaperone, exerts strikingly contrasting effects on the folding of non-native proteins as it transitions between a monomeric and a dimeric state. We used NMR spectroscopy to determine the atomic resolution structure of the 100-kDa dimeric TF. The structural data show that some of the substrate-binding sites are buried in the dimeric interface, explaining the lower affinity for protein substrates of the dimeric compared to the monomeric TF. Surprisingly, the dimeric TF associates faster with proteins and it exhibits stronger anti-aggregation and holdase activity than the monomeric TF. The structural data show that the dimer assembles in a way that substrate-binding sites in the two subunits form a large contiguous surface inside a cavity, thus accounting for the observed accelerated association with unfolded proteins. Our results demonstrate how the activity of a chaperone can be modulated to provide distinct functional outcomes in the cell.

Data availability

Atomic coordinates for the TF dimer structure have been deposited in the Protein Data Bank (ID 6D6S)

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Tomohide Saio

Department of Chemistry, Hokkaido University, Hokkaido, Japan

For correspondence
saio@sci.hokudai.ac.jp

Competing interests
The authors declare that no competing interests exist.
Soichiro Kawagoe

Graduate School of Chemical Sciences and Engineering, Hokkaido University, Hokkaido, Japan

Competing interests
The authors declare that no competing interests exist.
Koichiro Ishimori

Department of Chemistry, Hokkaido University, Hokkaido, Japan

Competing interests
The authors declare that no competing interests exist.
Charalampos G Kalodimos

Department of Structural Biology, St Jude Children's Research Hospital, Memphis, United States

For correspondence
babis.kalodimos@stjude.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6354-2796

Funding

National Institute of General Medical Sciences (GM122462)

Charalampos G Kalodimos

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.