Por favor, use este identificador para citar o enlazar este ítem:
http://hdl.handle.net/10609/137011
Título : | Cooperative stabilisation of 14-3-3 sigma protein-protein interactions via covalent protein modification |
Autoría: | Falcicchio, Marta Ward, Jake A. Chothia, Sara Y. Basran, Jaswir Mohindra, Alisha Macip, Salvador Roversi, Pietro Doveston, Richard G. |
Otros: | Universitat Oberta de Catalunya (UOC) |
Citación : | Falcicchio, M.; Ward, J.A.; Chothia, S.Y.; Basran, J.; Mohindra, A.; Macip, S.; Roversi, P.; Doveston, R.G. (2021). Cooperative stabilisation of 14-3-3o protein-protein interactions via covalent protein modification. Chem. Sci.,. 12(39), 12985-12992. doi: 10.1039/d1sc02120f |
Resumen : | 14-3-3 proteins are an important family of hub proteins that play important roles in many cellular processes via a large network of interactions with partner proteins. Many of these protein-protein interactions (PPI) are implicated in human diseases such as cancer and neurodegeneration. The stabilisation of selected 14-3-3 PPIs using drug-like 'molecular glues' is a novel therapeutic strategy with high potential. However, the examples reported to date have a number of drawbacks in terms of selectivity and potency. Here, we report that WR-1065, the active species of the approved drug amifostine, covalently modifies 14-3-3o at an isoform-unique cysteine residue, Cys38. This modification leads to isoform-specific stabilisation of two 14-3-3o PPIs in a manner that is cooperative with a well characterised molecular glue, fusicoccin A. Our findings reveal a novel stabilisation mechanism for 14-3-3o, an isoform with particular involvement in cancer pathways. This mechanism can be exploited to harness the enhanced potency conveyed by covalent drug molecules and dual ligand cooperativity. This is demonstrated in two cancer cell lines whereby the cooperative behaviour of fusicoccin A and WR-1065 leads to enhanced efficacy for inducing cell death and attenuating cell growth. |
Palabras clave : | proteins interaction stabilisation |
DOI: | 10.1039/d1sc02120f |
Tipo de documento: | info:eu-repo/semantics/article |
Fecha de publicación : | 21-oct-2021 |
Licencia de publicación: | http://creativecommons.org/licenses/by/3.0/es/ |
Aparece en las colecciones: | Articles Articles cientÍfics |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
Cooperative stabilisation of 14-3-3 protein-protein.pdf | 1,12 MB | Adobe PDF | Visualizar/Abrir |
Comparte:
Este ítem está sujeto a una licencia Creative Commons Licencia Creative Commons