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Folding pathway of an Ig domain is conserved on and off the ribosome
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0003-0426-3716
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Number of Authors: 112018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 48, p. E11284-E11293Article in journal (Refereed) Published
Abstract [en]

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-beta Ig 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.

Place, publisher, year, edition, pages
2018. Vol. 115, no 48, p. E11284-E11293
Keywords [en]
arrest peptide, fraction folded, mechanical force, molecular simulation, kinetic model
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-162838DOI: 10.1073/pnas.1810523115ISI: 000451351000015PubMedID: 30413621OAI: oai:DiVA.org:su-162838DiVA, id: diva2:1269390
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved

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Kudva, RenukaShilling, Patrick J.von Heijne, Gunnar
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