Waudby, CA;
Wlodarski, T;
Karyadi, M-E;
Cassaignau, AME;
Chan, SHS;
Wentink, AS;
Schmidt-Engler, JM;
... Christodoulou, J; + view all
(2018)
Systematic mapping of free energy landscapes of a growing filamin domain during biosynthesis.
Proceedings of the National Academy of Sciences
, 115
(39)
pp. 9744-9749.
10.1073/pnas.1716252115.
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Abstract
Cotranslational folding (CTF) is a fundamental molecular process that ensures efficient protein biosynthesis and minimizes the formation of misfolded states. However, the complexity of this process makes it extremely challenging to obtain structural characterizations of CTF pathways. Here, we correlate observations of translationally arrested nascent chains with those of a systematic C-terminal truncation strategy. We create a detailed description of chain length-dependent free energy landscapes associated with folding of the FLN5 filamin domain, in isolation and on the ribosome, and thus, quantify a substantial destabilization of the native structure on the ribosome. We identify and characterize two folding intermediates formed in isolation, including a partially folded intermediate associated with the isomerization of a conserved cis proline residue. The slow folding associated with this process raises the prospect that neighboring unfolded domains might accumulate and misfold during biosynthesis. We develop a simple model to quantify the risk of misfolding in this situation and show that catalysis of folding by peptidyl-prolyl isomerases is sufficient to eliminate this hazard.
Type: | Article |
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Title: | Systematic mapping of free energy landscapes of a growing filamin domain during biosynthesis |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1073/pnas.1716252115 |
Publisher version: | https://doi.org/10.1073/pnas.1716252115 |
Language: | English |
Additional information: | Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). |
Keywords: | cotranslational folding, molecular dynamics simulations, nuclear magnetic resonance, protein misfolding, tandem repeat protein |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
URI: | https://discovery.ucl.ac.uk/id/eprint/10056528 |
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