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The Folding Pathway of an Ig Domain is Conserved On and Off the Ribosome

Pengfei Tian, Annette Steward, Renuka Kudva, Ting Su, Patrick J. Shilling, Adrian A. Nickson, Jeffrey J. Hollins, Roland Beckmann, Gunnar Von Heijne, Robert B. Best, Jane Clarke
doi: https://doi.org/10.1101/253013
Pengfei Tian
1Laboratory of Chemical Physics, NIDDK, National Institutes of Health, 5 Memorial Drive, Bethesda, MD 20892-0520, USA.
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Annette Steward
2Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
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Renuka Kudva
3Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
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Ting Su
5Gene Center, Department of Biochemistry and Center for Integrated Protein Science Munich, CiPS-M, Feodor-Lynen-Strasse 25, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
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Patrick J. Shilling
3Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
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Adrian A. Nickson
2Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
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Jeffrey J. Hollins
2Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
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Roland Beckmann
5Gene Center, Department of Biochemistry and Center for Integrated Protein Science Munich, CiPS-M, Feodor-Lynen-Strasse 25, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
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Gunnar Von Heijne
3Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
4Science for Life Laboratory Stockholm University, Box 1031, SE-171 21 Solna, Sweden.
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Robert B. Best
1Laboratory of Chemical Physics, NIDDK, National Institutes of Health, 5 Memorial Drive, Bethesda, MD 20892-0520, USA.
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Jane Clarke
2Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
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Summary

Proteins that fold cotranslationally do so in a restricted configurational space, due to the volume occupied by the ribosome. Here, we investigate the cotranslational folding of an all-β immunoglobulin domain, titin I27, whose intrinsic folding mechanism has been extensively characterized. 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 ribosome, by essentially the same pathway as free I27, with only subtle shifts of critical contacts from the C to the N terminus.

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Posted January 24, 2018.
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The Folding Pathway of an Ig Domain is Conserved On and Off the Ribosome
Pengfei Tian, Annette Steward, Renuka Kudva, Ting Su, Patrick J. Shilling, Adrian A. Nickson, Jeffrey J. Hollins, Roland Beckmann, Gunnar Von Heijne, Robert B. Best, Jane Clarke
bioRxiv 253013; doi: https://doi.org/10.1101/253013
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The Folding Pathway of an Ig Domain is Conserved On and Off the Ribosome
Pengfei Tian, Annette Steward, Renuka Kudva, Ting Su, Patrick J. Shilling, Adrian A. Nickson, Jeffrey J. Hollins, Roland Beckmann, Gunnar Von Heijne, Robert B. Best, Jane Clarke
bioRxiv 253013; doi: https://doi.org/10.1101/253013

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