In-silico studies to analyse the possible interactions of CircPPP1R12A translated peptide with Mst proteins

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. •In silico studies show that the peptide translated from circPPP1R12A binds to the Mst proteins.•The binding occurs at the SARAH domain of Mst2.•For Mst1 binding is at the SARAH, as well as the Kinase domain.•This binding hinders the proper dimerization of Mst1/2 with Sav1 to prevent their activation.•It predicts the possible mechanism by which the peptide can deactivate the Mst pathway.