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Nature publication: Helper in protein folding prevents clumping

08 July 2013

Researchers from the University of Groningen and their colleagues from Amsterdam and Heidelberg have demonstrated that the TF1 chaperone protein actively accelerates the folding of newly produced proteins and stabilises the folded structure. This will help us understand a fundamental process in living cells: the correct folding of proteins. The research was published on 7 July 2013 in the scientific journal Nature.

A protein is like a long string of amino acids. This string quickly folds into a three-dimensional structure because, for example, certain amino acids are attracted to each other. The correct folding is essential to the protein’s function. Misfolding can cause the protein to clump, which is harmful to the cell.

Pulled apart

Chaperone proteins have an important role in the folding process. Some years ago the group of University of Groningen professor Arnold Driessen and the FOM AMOLF Institute in Amsterdam developed a technique to study the effect of chaperone proteins. This involves a system that slowly pulls apart a folded protein, with or without chaperones. The force required for this says something about the structure of the protein and the effect of the chaperone.

Stimulates folding

Tests with the model protein MBP (maltose binding protein) have shown that the trigger factor chaperone (TF1) stabilises the folded structure of this protein. It takes considerably more effort to pull apart the protein with TF1 than without this chaperone. ‘We knew that TF1 binds to still incomplete proteins that come from the ribosome, the protein factory of the cell’, says Driessen. ‘But opinion was divided about the exact function of TF1.’ One school of thought was that TF1 only ironed out a small ‘wrinkle’ in a protein and nothing else, while another was that TF1 actually stimulates the folding of proteins. ‘Our work shows that the latter is the case’.

Prevents protein clumps

MBP is a relatively small protein. The researchers therefore also studied a large protein consisting of four interlinked MBP proteins. ‘If you pull it apart and then let it fold again, you get a structure that you can no longer pull apart’, says Driessen. ‘This indicates that the protein has clumped in such a way that you cannot disentangle it’. The addition of TF1 prevents this. With TF1 the protein folds neatly back into its original shape. ‘This shows that TF1 prevents protein clumping’.

Actively stimulates

This is the first time that anyone has directly observed how a chaperone actively stimulates protein folding. Five years ago Driessen’s group was also the first to show, with the same system, that another chaperone, SecB, temporarily keeps the proteins in the unfolded shape. ‘This makes it easier to transport these proteins out of the cell’.

Right shape

Driessen’s focus is on how cells secrete their proteins. Chaperones help here by ensuring that the proteins keep the right shape (folded or unfolded). But the knowledge generated by his research can also be used in the study of diseases that are caused by protein misfolding. ‘Our technique is providing important information here, and in the future it will tell us how chaperone proteins work together to achieve the right folding’.

Further information: Prof. Arnold Driessen

Reference: Reshaping of a protein's conformational search by the chaperone Trigger Factor, Alireza Mashaghi, Günter Kramer, Philipp Bechtluft, Beate Zachmann-Brand, Arnold J. M. Driessen, Bernd Bukau, and Sander J. Tans, Nature, 7 July 2013.

DOI: 10.1038/nature12293

The following funding acknowledgements from the authors appear at the end of the paper: Work in the laboratory of S.J.T. is part of the research program of the Stichting voor Fundamenteel Onderzoek der Materie (FOM), which is financially supported by the Nederlandse Organisatie voor Wetenschappelijke Onderzoek (NWO). Work in the laboratory of B.B. and G.K. is supported by grants from the Deutsche Forschungsgemeinschaft (SFB 638, FOR967).

Last modified:13 March 2020 02.15 a.m.
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