Camilloni, C;
Sala, BM;
Sormanni, P;
Porcari, R;
Corazza, A;
De Rosa, M;
Zanini, S;
... Ricagno, S; + view all
(2016)
Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability.
Scientific Reports
, 6
, Article 25559. 10.1038/srep25559.
![[thumbnail of Published article]](https://discovery.ucl.ac.uk/style/images/fileicons/text.png) |
Text (Published article)
Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability.pdf - Published Version Download (1MB) |
Preview |
Text (Supporting Figures and Tables)
Camilloni_Rational design of mutations that change the aggregation rate of a protein Supplementary.pdf Download (370kB) | Preview |
Abstract
A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation-prone exposed surface of wild-type and W60G β2m modifying their aggregation propensity. These results allowed us to pinpoint the role of dynamics in β2m aggregation and to provide a new strategy to tune protein aggregation by modulating the exposure of aggregation-prone residues.
| Type: | Article |
|---|---|
| Title: | Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/srep25559 |
| Publisher version: | http://dx.doi.org/10.1038/srep25559 |
| 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: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, Replica-averaged Metadynamics, Amyloid Formation, Beta(2)-microglobulin, Beta-2-microglobulin, State, Nmr, Association, Edge, Competition, Solubility |
| 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 > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1514533 |
Archive Staff Only
 |
View Item |
