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Updated: Aug 24, 2025
Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions
Published on: January 26, 2024
In-silico studies to analyse the possible interactions of CircPPP1R12A translated peptide with Mst proteins
Tanusree Mookherjee1, Angshuman Bagchi1, Rita Ghosh1
1Department of Biochemistry & Biophysics, University of Kalyani, Kalyani, 741235, West Bengal, India.
Abstract:
The Mammalian sterile 20 kinase (Mst) pathway controls organ development by regulating cell proliferation through apoptosis and has a noncanonical role in cancer. Overexpression of the peptide translated from circular RNA, circPPP1R12A, corelated with the activation of YAP, an oncogene whose expression is triggered upon dysregulation of Mst signalling. The exact mode of molecular interaction(s) leading to inactivation of the Mst pathway by this peptide is hitherto unknown. Mst1 and Mst2 are two prime proteins that require dimerization with their scaffold protein, Sav1 at the early step of Mst signalling. We have investigated the interaction of Mst1/2 proteins with this peptide using molecular docking and molecular dynamics simulation studies. The amino acids involved in binding of the peptide were identified and a comparison between the binding interfaces of Mst1/2 - peptide with Mst1/2 - Sav1 complexes indicated that the binding of the peptide to these Mst proteins may prevent the interactions of these proteins with Sav1. Studying the possible binding modes of Sav1 to the Mst proteins already complexed with the peptide further confirmed that the binding of the peptide may hinder their activation. The in-silico study indicated for the first time the possible molecular mechanism of how the peptide can promote cancer by interfering with the Mst pathway.
Insights
A novel peptide from circPPP1R12A may promote cancer by disrupting the Mammalian sterile 20 kinase (Mst) pathway. This study reveals how the peptide binds Mst1/2 proteins, potentially blocking their interaction with Sav1 and hindering pathway activation.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncology
Background:
- The Mammalian sterile 20 kinase (Mst) pathway is crucial for organ development, regulating cell proliferation and apoptosis.
- Dysregulation of the Mst pathway and overexpression of YAP, an oncogene, are implicated in cancer.
- A peptide derived from circular RNA, circPPP1R12A, has been correlated with YAP activation, suggesting a role in Mst pathway interference.
Purpose of the Study:
- To elucidate the molecular mechanism by which the circPPP1R12A-derived peptide interacts with and potentially inactivates the Mst signaling pathway.
- To investigate the binding interactions between the Mst1/2 proteins and the circPPP1R12A peptide using computational methods.
Main Methods:
- In-silico molecular docking and molecular dynamics simulations were employed to study protein-peptide interactions.
- Analysis of amino acid residues involved in the binding interface between Mst1/2 and the peptide.
- Comparison of binding interfaces of Mst1/2-peptide complexes with Mst1/2-Sav1 complexes.
Main Results:
- The study identified specific amino acids involved in the binding of the circPPP1R12A peptide to Mst1 and Mst2 proteins.
- Computational analysis suggests that the peptide binding to Mst1/2 may sterically hinder the essential dimerization with the scaffold protein Sav1.
- Further simulations indicate that Sav1 binding to Mst1/2 is impeded when the peptide is already bound, suggesting a mechanism for pathway inactivation.
Conclusions:
- This in-silico study provides the first proposed molecular mechanism for how the circPPP1R12A peptide may promote cancer by interfering with Mst pathway signaling.
- The findings highlight a potential therapeutic target by suggesting that blocking the interaction between the peptide and Mst proteins could offer a strategy to counteract Mst pathway dysregulation in cancer.
