Local frustration determines loop opening during the catalytic cycle of an oxidoreductase
- University of Oxford, United Kingdom
- University of Texas at Austin, United States
- NCSR Demokritos, Greece
- University of Neuchatel, Switzerland
Abstract
Local structural frustration, the existence of mutually exclusive competing interactions, may explain why some proteins are dynamic while others are rigid. Frustration is thought to underpin biomolecular recognition and the flexibility of protein binding sites. Here we show how a small chemical modification, the oxidation of two cysteine thiols to a disulfide bond, during the catalytic cycle of the N-terminal domain of the key bacterial oxidoreductase DsbD (nDsbD), introduces frustration ultimately influencing protein function. In oxidized nDsbD, local frustration disrupts the packing of the protective cap-loop region against the active site allowing loop opening. By contrast, in reduced nDsbD the cap loop is rigid, always protecting the active-site thiols from the oxidizing environment of the periplasm. Our results point towards an intricate coupling between the dynamics of the active-site cysteines and of the cap loop which modulates the association reactions of nDsbD with its partners resulting in optimized protein function.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Christina Redfield
Funding
Biotechnology and Biological Sciences Research Council (BB/F01709X/1)
- Lukas L Stelzl
Biotechnology and Biological Sciences Research Council (BB/R00126X/1)
- Mark SP Sansom
Wellcome (208361/Z/17/Z)
- Mark SP Sansom
Wellcome (079440)
- Christina Redfield
Wellcome (092532/Z/10/Z)
- Stuart J Ferguson
- Christina Redfield
Swiss National Science Foundation (P300PA_167703)
- Diego Gonzalez
Swiss National Science Foundation (PZ00P3_180142)
- Diego Gonzalez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Lewis E Kay, University of Toronto, Canada
Version history
- Received: December 21, 2019
- Accepted: June 21, 2020
- Accepted Manuscript published: June 22, 2020 (version 1)
- Version of Record published: July 9, 2020 (version 2)
Copyright
© 2020, Stelzl et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Local frustration determines loop opening during the catalytic cycle of an oxidoreductase
eLife 9:e54661.
https://doi.org/10.7554/eLife.54661
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