Pucheta-Martinez, E;
D'Amelio, N;
Lelli, M;
Martinez-Torrecuadrada, JL;
Sudol, M;
Saladino, G;
Gervasio, FL;
(2016)
Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome.
Scientific Reports
, 6
(30293)
10.1038/srep30293.
![[thumbnail of srep30293.pdf]](https://discovery-pp.ucl.ac.uk/style/images/fileicons/text.png) |
Text
srep30293.pdf Download (1MB) |
Abstract
WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function.
| Type: | Article |
|---|---|
| Title: | Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/srep30293 |
| Publisher version: | http://dx.doi.org/10.1038/srep30293 |
| 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, SYNDROME PROTEIN PQBP1, CHEMICAL-SHIFT INDEX, STRUCTURAL-ANALYSIS, RENPENNING SYNDROME, LIGAND RECOGNITION, MENTAL-RETARDATION, MISSENSE MUTATION, BETA-HAIRPIN, BINDING, PROLINE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1514064 |
Archive Staff Only
 |
View Item |
