Folding pathway of an Ig domain is conserved on and off the ribosome.
Nickson, Adrian A
Hollins, Jeffrey J
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Tian, P., Steward, A., Kudva, R., Su, T., Shilling, P. J., Nickson, A. A., Hollins, J. J., et al. (2018). Folding pathway of an Ig domain is conserved on and off the ribosome.. Proceedings of the National Academy of Sciences of the United States of America, 115 (48), E11284-E11293. https://doi.org/10.1073/pnas.1810523115
Proteins that fold cotranslationally may do so in a restricted configurational space, due to the volume occupied by the ribosome. How does this environment, coupled with the close proximity of the ribosome, affect the folding pathway of a protein? Previous studies have shown that the cotranslational folding process for many proteins, including small, single domains, is directly affected by the ribosome. Here, we investigate the cotranslational folding of an all-β immunoglobulin domain, titin I27. Using an arrest peptide-based assay and structural studies by cryo-EM, we show that I27 folds in the mouth of the ribosome exit tunnel. Simulations that use a kinetic model for the force-dependence of escape from arrest, accurately predict the fraction of folded protein as a function of length. We used these simulations to probe the folding pathway on and off the ribosome. Our simulations - which also reproduce experiments on mutant forms of I27 - show that I27 folds, while still sequestered in the mouth of the ribosome exit tunnel, by essentially the same pathway as free I27, with only subtle shifts of critical contacts from the C to the N terminus.
Ribosomes, Humans, Protein Biosynthesis, Protein Folding, Kinetics, Models, Molecular, Connectin
Wellcome Trust (095195/Z/10/Z)
Embargo Lift Date
External DOI: https://doi.org/10.1073/pnas.1810523115
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286341
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/