KRAS K104 modification affects the KRAS-GEF interaction and mediates cell growth and motility.

Mutant RAS genes play an important role in regulating tumors through lysine residue 104 to impair GEF-induced nucleotide exchange, but the regulatory role of KRAS K104 modification on the KRAS mutant remains unclear. Therefore, we simulated the acetylation site on the KRAS three-dimensional protein structure, including KRAS, KRAS and KRAS, and determined their trajectories and binding free energy with GEF. KRAS induced structural changes in the α2- and α3-helices, promoted KRAS instability and hampered GEF binding (ΔΔG = 6.14 kJ/mol). We found decreased binding to the Raf1 RBD by KRAS and reduced cell growth, invasion and migration. Based on whole-genome cDNA microarray analysis, KRAS decreased expression of NPIPA2, DUSP1 and IL6 in lung and ovarian cancer cells. This study reports computational and experimental analyses of Lys104 of KRAS and GEF, and the findings provide a target for exploration for future treatment.