Hassi, Niina K;
Weston, Timir;
Rinaldi, Giulia;
Ng, Joseph C;
Smahi, Asma;
Twelves, Sophie;
Davan-Wetton, Camilla;
... Capon, Francesca; + view all
(2023)
in-silico and in-vitro analysis of IL36RN mutations reveals critical residues for the function of the interleukin-36 receptor complex.
Journal of Investigative Dermatology
10.1016/j.jid.2023.06.191.
(In press).
Preview |
Text
Ng_in-silico and in-vitro analysis of IL36RN mutations reveals critical residues for the function of the interleukin-36 receptor complex_Pre-proof.pdf - Accepted Version Download (3MB) | Preview |
Abstract
Generalized pustular psoriasis (GPP) is a potentially life-threatening skin disease, associated with IL36RN mutations. IL36RN encodes the interleukin (IL)-36 receptor antagonist (IL-36Ra), a protein that downregulates the activity of IL-36 cytokines by blocking their receptor (IL-36R). While GPP can be treated with IL-36R inhibitors, the structural underpinnings of the IL-36Ra/IL-36R interaction remain poorly understood. Here, we sought to address this question by systematically investigating the effects of IL36RN mutations. We experimentally characterized the effects of 30 IL36RN variants on protein stability. In parallel, we used a machine-learning tool (Rhapsody) to analyse the IL-36Ra three-dimensional structure and predict the impact of all possible amino acid substitutions. This integrated approach identified 21 amino acids that are essential to IL-36Ra stability. We next investigated the effects of IL36RN changes on IL-36Ra/IL-36R binding and IL-36R signalling. By combining in-vitro assays and machine-learning with a second programme (mCSM), we identified 13 amino acids that are critical to IL-36Ra/IL36R engagement. Finally, we experimentally validated three representative predictions, further confirming the reliability of Rhapsody and mCSM. These findings shed light on the structural determinants of IL-36Ra activity, with potential to facilitate the design of new IL-36 inhibitors and aid the interpretation of IL36RN variants in diagnostic settings.
| Type: | Article |
|---|---|
| Title: | in-silico and in-vitro analysis of IL36RN mutations reveals critical residues for the function of the interleukin-36 receptor complex |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jid.2023.06.191 |
| Publisher version: | https://doi.org/10.1016/j.jid.2023.06.191 |
| Language: | English |
| Additional information: | This is an Open Access article published under a Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). |
| 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/10175327 |
Archive Staff Only
 |
View Item |
