Conserved residues at the MAPKs binding interfaces that regulate transcriptional machinery

<div><p>Signaling through c-Raf downstream pathways is the crucial subject of extensive studies because over expressed or mutated genes in this pathway lead to a variety of human cancers. On the basis of cellular localization, this pathway has been sub-divided into two cascades. The first RAF1-MEK1-ERK2 cascade which remains in the cytosol, whereas the second MEK1-ERK2-RSKs transduces into the nucleus and regulates the transactivation function. But how a few amino acids critically regulate the transcriptional function remains unclear. In this paper, we have performed <i>in silico</i> studies to unravel how atomic complexities at the MEK1-ERK2-RSKs pathways intercedes different functional responses. The secondary structure of the ERK, RSKs have been modeled using Jpred3, PSI-PHRED, protein modeler, and Integrated sequence analyzer from Discovery Studio software. Peptides of RSKs isozymes (RSK1/2/3/4) were built and docked on ERK2 structure using ZDOCK module. The hydropathy index for the RSKs molecules was determined using the KYTE–DOOLITTLE plot. The simulations of complex molecules were carried out using a CHARMM force field. The protein–protein interactions (PPIs) in different cascade of MAP kinase (MAPK) have been shown to be similar to those predicted <i>in vivo</i>. PPIs elucidate that the amino acids located at the conserved domains of MAPK pathways are responsible for transactivation functions.</p></div>