3 May 2018

Surprising end of longstanding belief

Chaperones just prepare proteins for folding on their own

Tania Morán Luengo and Stefan Rüdiger from Utrecht University
PhD candidate Tania Morán Luengo and research leader Stefan Rüdiger from Utrecht University

The proteins in our cells are produced as long chains of amino acids that must fold precisely into their final shape. The key players in this folding process are the so-called molecular chaperones; protein helpers that make sure this process is successful. Researchers from Utrecht University, in close collaboration with colleagues from Heidelberg University, have at last uncovered how the two most important chaperone families, Hsp70 and Hsp90, cooperate in this folding process. Surprisingly, it turns out they do not actively assist in the folding, as scientists had long assumed. Instead, they simply prepare the proteins for spontaneous, productive folding. This breakthrough in understanding the functioning of the Hsp70-Hsp90 cascade was published only by Molecular Cell on 3 May.

Incorrectly folded proteins can result in serious diseases, such as Cystic Fibrosis and many neurodegenerative diseases like Alzheimer’s. Scientists have long known that Hsp70 and Hsp90 play a key role in this folding process, and that Hsp90 acts downstream of Hsp70. However, the actual mechanism by which they fold a protein has remained enigmatic.

Longstanding belief

PhD candidate Tania Morán Luengo from Utrecht University has recently demonstrated that the chaperone Hsp70 binds to the young protein, protecting it while also preventing it from folding. Then Hsp90 breaks the Hsp70 block, which allows the protein to continue folding into the correct state all by itself. This discovery signalled the surprising end of the longstanding belief that chaperones fold proteins. For her outstanding work, Morán Luengo was selected as Bijvoet Center PhD Student of the Year.

This stop-start mechanism is conserved from bacteria to man. Many diseases rely on the final active shape of proteins. Thus, researchers working on therapies that target the folding process, finally know what to look for.
Stefan Rüdiger

Fast-acting relay team

The illustration below shows how the molecular chaperones Hsp70 and Hsp90 form a fast-acting relay team to prepare proteins to fold into their active state on their own. Hsp70 recognizes short hydrophobic stretches (yellow), exposed in the unfolded protein. Hsp90 acts downstream from Hsp70 and facilitates forming the folding intermediate, which slowly turns into the native state, free of further chaperone action.

The molecular chaperones Hsp70 and Hsp90 form a fast-acting relay team to prepare proteins to fold into their active state on their own.

Novel idea

Research leader Dr. Stefan Rüdiger from Utrecht University got a glimpse of this novel idea while preparing to teach a course about the subject. Hsp70 binds to hydrophobic amino acids, protecting them from sticking together until they are hidden inside the final protein structure. He suddenly realised that the way Hsp70 binds to its substrates therefore could not contribute to protein folding, but rather inhibits it instead.

Inhibitor, not promotor

The researchers then set out to analyse the folding process, observing that concentrations of Hsp70 in the range of those present in our cells inhibited protein folding. “This inferred that Hsp70 is not a promoter, but in fact an effective inhibitor of the folding process”, Rüdiger explains. His group teamed up with the laboratory of Prof. Matthias Mayer at Heidelberg University to test this hypothesis experimentally. They demonstrated that the presence of Hsp90 at this point is critical for the folding process to occur. Hsp90 enables the protein to break out of the Hsp70 deadlock to fold in its right shape – on its own.

Cover van Molecular Cell met illustratie van het onderzoek van Stefan Rüdiger c.s.

Molecular Cell choose an illustration of this research for its cover. The artwork was done by Stefan Rüdiger (acryl on canvas). It represents that the conserved Hsp70 and Hsp90 chaperones form a cascade that is only active in the first, red-hot minutes of the folding process. The subsequent passage through the trail to the native state is long and slow - and free of interference by chaperones.


Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System
Tania Morán Luengo*, Roman Kityk, Matthias P. Mayer & Stefan Rüdiger*
Molecular Cell, 26 April, DOI: 10.1016/j.molcel.2018.03.028
*Affiliated with Utrecht University

This research was funded by the Initial Training Network ManiFold of the Marie-Curie Programme of the European Union, by a ZonMW TOP grant, by Alzheimer Nederland and by the Deutsche Forschungsgemeinschaft. It is conductied within the research theme Science for Life, part of Utrecht University’s interdisciplinary research programme Life Sciences.​

Read more about the research by Stefan Rüdiger

Clumping proteins disable anti-cancer- network (publication in Nature Structural and Molecular Biology)

Mystery of client selection of chaperone Hsp90 solved (publication in Cell)