Reshaping of the conformational search of a protein by the chaperone trigger factor

• Published in: Nature (London) 2013-08, Vol.500 (7460), p.98-101
• Main Authors: Mashaghi, Alireza, Kramer, Günter, Bechtluft, Philipp, Zachmann-Brand, Beate, Driessen, Arnold J. M., Bukau, Bernd, Tans, Sander J.
• Format: Article
• Language: English
• Subjects: 631/45/470/1981; 631/57/2265; Binding proteins; Binding Sites; Biophysics; Conformational analysis; Cytosol - metabolism; E coli; Escherichia coli - chemistry; Escherichia coli - metabolism; Escherichia coli Proteins - metabolism; Humanities and Social Sciences; letter; Maltose-Binding Proteins - biosynthesis; Maltose-Binding Proteins - chemistry; Maltose-Binding Proteins - metabolism; Methods; Models, Molecular; Molecular chaperones; Molecular Chaperones - metabolism; multidisciplinary; Optical Tweezers; Peptides; Peptides - chemistry; Peptides - metabolism; Peptidylprolyl Isomerase - metabolism; Physiological aspects; Polypeptides; Properties; Protein Biosynthesis; Protein Conformation; Protein Folding; Protein Refolding; Protein research; Protein Stability; Protein Structure, Tertiary; Ribosomes - metabolism; Science; Spectroscopy, Fourier Transform Infrared
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12293

The bacterial chaperone named trigger factor is found to stabilize protein folding intermediates that eventually convert to the native state, suggesting that chaperones play a direct role in instructing protein folding. How trigger factor prevents protein misfolding Molecular chaperones prevent aggregation between nascent protein chains but whether they also assist an individual chain's folding cannot be tested with 'bulk' biochemistry. Now, by using laser tweezers to pull on the ends of single maltose binding protein (MBP) molecules, Sander Tans and colleagues demonstrate that the bacterial chaperone known as trigger factor stabilizes folding intermediates that eventually convert to the native state. The results suggest that chaperones have a direct role in instructing co-translational folding. Protein folding is often described as a search process, in which polypeptides explore different conformations to find their native structure. Molecular chaperones are known to improve folding yields by suppressing aggregation between polypeptides before this conformational search starts 1 , 2 , as well as by rescuing misfolds after it ends 1 , 3 . Although chaperones have long been speculated to also affect the conformational search itself—by reshaping the underlying folding landscape along the folding trajectory 4 , 5 —direct experimental evidence has been scarce so far. In Escherichia coli , the general chaperone trigger factor 6 , 7 , 8 (TF) could play such a role. TF has been shown to interact with nascent chains at the ribosome 9 , 10 , with polypeptides released from the ribosome into the cytosol 11 , and with fully folded proteins before their assembly into larger complexes 12 . To investigate the effect of TF from E. coli on the conformational search of polypeptides to their native state, we investigated individual maltose binding protein (MBP) molecules using optical tweezers. Here we show that TF binds folded structures smaller than one domain, which are then stable for seconds and ultimately convert to the native state. Moreover, TF stimulates native folding in constructs of repeated MBP domains. The results indicate that TF promotes correct folding by protecting partially folded states from distant interactions that produce stable misfolded states. As TF interacts with most newly synthesized proteins in E. coli , we expect these findings to be of general importance in understanding protein folding pathways.