Plessa, E;
Chu, LP;
Chan, SHS;
Thomas, OL;
Cassaignau, AME;
Waudby, CA;
Christodoulou, J;
(2021)
Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein.
Nature Communications
, 12
(1)
, Article 6447. 10.1038/s41467-021-26531-1.
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Cabrita_Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein_VoR.pdf - Published Version Download (1MB) | Preview |
Abstract
During biosynthesis, proteins can begin folding co-translationally to acquire their biologically-active structures. Folding, however, is an imperfect process and in many cases misfolding results in disease. Less is understood of how misfolding begins during biosynthesis. The human protein, alpha-1-antitrypsin (AAT) folds under kinetic control via a folding intermediate; its pathological variants readily form self-associated polymers at the site of synthesis, leading to alpha-1-antitrypsin deficiency. We observe that AAT nascent polypeptides stall during their biosynthesis, resulting in full-length nascent chains that remain bound to ribosome, forming a persistent ribosome-nascent chain complex (RNC) prior to release. We analyse the structure of these RNCs, which reveals compacted, partially-folded co-translational folding intermediates possessing molten-globule characteristics. We find that the highly-polymerogenic mutant, Z AAT, forms a distinct co-translational folding intermediate relative to wild-type. Its very modest structural differences suggests that the ribosome uniquely tempers the impact of deleterious mutations during nascent chain emergence. Following nascent chain release however, these co-translational folding intermediates guide post-translational folding outcomes thus suggesting that Z’s misfolding is initiated from co-translational structure. Our findings demonstrate that co-translational folding intermediates drive how some proteins fold under kinetic control, and may thus also serve as tractable therapeutic targets for human disease.
| Type: | Article |
|---|---|
| Title: | Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-021-26531-1 |
| Publisher version: | https://doi.org/10.1038/s41467-021-26531-1 |
| Language: | English |
| Additional information: | © 2021 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Protein aggregation, Ribosome, Solution-state NMR |
| 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/10138450 |
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