KRAS K104 modification affects the KRAS(G12D)-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(G12D) mutant remains unclear. Therefore, we simulated the acetylation site on the KRAS(G12D) three-dimensio...

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Detalles Bibliográficos
Autores principales: Chen, Chih-Chieh, Hsu, Chia-Yi, Lin, Hsiao-Yun, Zeng, Hong-Qi, Cheng, Kuang-Hung, Wu, Chia-Wei, Tsai, Eing-Mei, Hsieh, Tsung-Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567070/
https://www.ncbi.nlm.nih.gov/pubmed/33060649
http://dx.doi.org/10.1038/s41598-020-74463-5
Descripción
Sumario: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 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(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.

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