Porebski, BT;
Keleher, S;
Hollins, JJ;
Nickson, AA;
Marijanovic, EM;
Borg, NA;
Costa, MGS;
... Buckle, AM; + view all
(2016)
Smoothing a rugged protein folding landscape by sequence-based redesign.
Scientific Reports
, 6
, Article 33958. 10.1038/srep33958.
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Abstract
The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation. Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and misfolding. Serpins exist in a metastable state that undergoes a major conformational change in order to inhibit proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding, which underlies misfolding diseases such as α1-antitrypsin deficiency. To investigate how serpins balance function and folding, we used consensus design to create conserpin, a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant. Characterization of its structure, folding and dynamics suggest that consensus design has remodeled the folding landscape to reconcile competing requirements for stability and function. This approach may offer general benefits for engineering functional proteins that have risky folding landscapes, including the removal of aggregation-prone intermediates, and modifying scaffolds for use as protein therapeutics.
| Type: | Article |
|---|---|
| Title: | Smoothing a rugged protein folding landscape by sequence-based redesign |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/srep33958 |
| Publisher version: | http://dx.doi.org/10.1038/srep33958 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | CRYSTAL-STRUCTURE, CONFORMATIONAL DISEASE, BETA-SHEET, F-HELIX, SERPIN ALPHA(1)-ANTITRYPSIN, MOLECULAR-MECHANISM, GLOBULAR PROTEIN, NEGATIVE DESIGN, HIGH-RESOLUTION, REACTIVE LOOP |
| 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 Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1518350 |
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