Engineering β-catenin-derived peptides for α-catenin binding
The complex formed by the β-catenin and α-catenin adaptor proteins acts as a molecular bridge that enables E-cadherin-based cell–cell adhesion assembly and maintenance in the epithelial tissue. This occurs through the interaction between the intracellular domain of E-cadherin and β-catenin on the one hand and between F-actin and α-catenin on the other hand. In addition to its role in cell–cell adhesion formation, it has been reported that E-cadherin mediates breast cancer cell metastasis to distant organs. Therefore, development of biomaterials such as peptides with ability to modulate the interaction between β-catenin and α-catenin presents an opportunity to modulate cell–cell adhesion. Here, we have performed computational and experimental analysis to develop β-catenin-derived peptides with the ability to bind α-catenin. Specifically, we analyzed the available β- and α-catenin complex structure and identified residues on β-catenin having potential to form new interactions upon mutation. We tested the wild-type (WT) and mutant β-catenin-derived peptides for their binding to α-catenin using conventional and steered molecular dynamics simulations, revealing an increased interaction of P128E and M131E mutant peptides. We then designed a Bioluminescence Resonance Energy Transfer (BRET)-based assay to monitor binding of the β-catenin-derived peptides with α-catenin, which revealed similar binding affinities of the WT and mutant β-catenin-derived peptides. Further, expression of the WT and the M131E mutant peptide resulted in a change in the aspect ratio of the cells suggestive of their ability to affect cell–cell adhesion. We envisage that the β-catenin-derived peptides engineered here will find application in blocking the interaction between β-catenin and α-catenin and, thus, modulate E-cadherin adhesion, which may lead to potential therapeutic avenue in abrogating E-cadherin-mediated metastasis of invasive breast cancer cells.
Other Information
Published in: Emergent Materials
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: https://dx.doi.org/10.1007/s42247-024-00663-8
Funding
Open Access funding provided by the Qatar National Library.
Hamad Bin Khalifa University (HBKU-INT-VPR-TG-02–09).
History
Language
- English
Publisher
Springer NaturePublication Year
- 2024
License statement
This Item is licensed under the Creative Commons Attribution 4.0 International License.Institution affiliated with
- Hamad Bin Khalifa University
- College of Health and Life Sciences - HBKU
- Carnegie Mellon University in Qatar
- Academic Resource Center - CMU-Q