Evaluation of Pathogenicity and Structural Alterations for the Mutations Identified in the Conserved Region of the C-Terminal Kinase Domain of Human-Ribosomal S6 Kinase 1.

Abstract

Human-ribosomal s6 kinase 1 (h-RSK1) is an effector kinase of the Ras/MAPK signaling pathway, which is involved in the regulation of the cell cycle, proliferation, and survival. RSKs comprise two functionally distinct kinase domains at the N-terminal (NTKD) and C-terminal (CTKD) separated by a linker region. The mutations in RSK1 may have the potential to provide an extra benefit to the cancer cell to proliferate, migrate, and survive. The present study focuses on evaluating the structural basis for the missense mutations identified at the C-terminal kinase domain of human-RSK1. A total of 139 mutations reported on RSK1 were retrieved from cBioPortal, where 62 were located at the CTKD region. Furthermore, 10 missense mutations Arg434Pro, Thr701Met, Ala704Thr, Arg725Trp, Arg726Gln, His533Asn, Pro613Leu, Ser720Cys, Arg725Gln, and Ser732Phe were predicted to be deleterious using in silico tools. To our observation, these mutations are located in the evolutionarily conserved region of RSK1 and shown to alter the inter- and intramolecular interactions and also the conformational stability of RSK1-CTKD. The molecular dynamics (MD) simulation study further revealed that the five mutations Arg434Pro, Thr701Met, Ala704Thr, Arg725Trp, and Arg726Gln showed maximum structural alterations in RSK1-CTKD. Thus, based on the in silico and MD simulation analysis, it can be concluded that the reported mutations may serve as potential candidates for further functional studies.