KRAS K104 modification affects the KRAS^G12D-GEF interaction and mediates cell growth and motility.

ABSTRACT: 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^G12D mutant remains unclear. Therefore, we simulated the acetylation site on the KRAS^G12D three-dimensional protein structure, including KRAS^G12D, KRAS^G12D/K104A and KRAS^G12D/K104Q, and determined their trajectories and binding free energy with GEF. KRAS^G12D/K104Q induced structural changes in the ?2- and ?3-helices, promoted KRAS instability and hampered GEF binding (??G?=?6.14 kJ/mol). We found decreased binding to the Raf1 RBD by KRAS^G12D/K104Q and reduced cell growth, invasion and migration. Based on whole-genome cDNA microarray analysis, KRAS^G12D/K104Q decreased expression of NPIPA2, DUSP1 and IL6 in lung and ovarian cancer cells. This study reports computational and experimental analyses of Lys104 of KRAS^G12D and GEF, and the findings provide a target for exploration for future treatment.

SUBMITTER: Chen CC 

PROVIDER: S-EPMC7567070 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature