Protein unfolding as a switch from self-recognition to high-affinity client binding

Bastian Groitl, Scott Horowitz, Karl A.T. Makepeace, Evgeniy V. Petrotchenko, Christoph H. Borchers, Dana Reichmann, James C.A. Bardwell, Ursula Jakob*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Stress-specific activation of the chaperone Hsp33 requires the unfolding of a central linker region. This activation mechanism suggests an intriguing functional relationship between the chaperone € s own partial unfolding and its ability to bind other partially folded client proteins. However, identifying where Hsp33 binds its clients has remained a major gap in our understanding of Hsp33 € s working mechanism. By using site-specific Fluorine-19 nuclear magnetic resonance experiments guided by in vivo crosslinking studies, we now reveal that the partial unfolding of Hsp33 € s linker region facilitates client binding to an amphipathic docking surface on Hsp33. Furthermore, our results provide experimental evidence for the direct involvement of conditionally disordered regions in unfolded protein binding. The observed structural similarities between Hsp33 € s own metastable linker region and client proteins present a possible model for how Hsp33 uses protein unfolding as a switch from self-recognition to high-affinity client binding.

Original languageAmerican English
Article number10357
JournalNature Communications
StatePublished - 20 Jan 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank R. Mehl and the Unnatural Protein Facility for helpful advice and for providing the p-CNF vector, P. Schultz for providing the pEVOL vector, C. Lennon for helpful discussion on BPA crosslinking and C. Cremers for reading the manuscript, general technical advice and fruitful discussions. We thank the Genome Canada and Genome British Columbia Science and Technology Innovation Centre funding and The Natural Sciences and Engineering Research Council of Canada grant (to C.H.B.). This research was funded by the National Institutes of Health Grant GM065318 (to U.J.). J.C.A.B is a Howard Hughes Investigator.


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