The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B

Shaoyong Lu, Hyunbum Jang, Ruth Nussinov*, Jian Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

Abstract

Ras mediates cell proliferation, survival and differentiation. Mutations in K-Ras4B are predominant at residues G12, G13 and Q61. Even though all impair GAP-assisted GTP → GDP hydrolysis, the mutation frequencies of K-Ras4B in human cancers vary. Here we aim to figure out their mechanisms and differential oncogenicity. In total, we performed 6.4 μs molecular dynamics simulations on the wild-type K-Ras4B (K-Ras4BWT-GTP/GDP) catalytic domain, the K-Ras4BWT-GTP-GAP complex, and the mutants (K-Ras4BG12C/G12D/G12V-GTP/GDP, K-Ras4BG13D-GTP/GDP, K-Ras4BQ61H-GTP/GDP) and their complexes with GAP. In addition, we simulated 'exchanged' nucleotide states. These comprehensive simulations reveal that in solution K-Ras4BWT-GTP exists in two, active and inactive, conformations. Oncogenic mutations differentially elicit an inactive-to-active conformational transition in K-Ras4B-GTP; in K-Ras4BG12C/G12D-GDP they expose the bound nucleotide which facilitates the GDP-to-GTP exchange. These mechanisms may help elucidate the differential mutational statistics in K-Ras4B-driven cancers. Exchanged nucleotide simulations reveal that the conformational transition is more accessible in the GTP-to-GDP than in the GDP-to-GTP exchange. Importantly, GAP not only donates its R789 arginine finger, but stabilizes the catalytically-competent conformation and pre-organizes catalytic residue Q61; mutations disturb the R789/Q61 organization, impairing GAP-mediated GTP hydrolysis. Together, our simulations help provide a mechanistic explanation of key mutational events in one of the most oncogenic proteins in cancer.

Original languageEnglish
Article number21949
JournalScientific Reports
Volume6
DOIs
StatePublished - 23 Feb 2016

Funding

FundersFunder number
National Institutes of HealthHHSN261200800001E
National Cancer InstituteZIABC010441
Frederick National Laboratory for Cancer Research
National Natural Science Foundation of China81473137, 81322046, 81302698
Program for New Century Excellent Talents in UniversityNCET-12-0355
Shanghai Minhang Health And Family Planning Commission20154Y0058
National Basic Research Program of China (973 Program)2015CB910403
Shanghai Rising-Star Program13QA1402300

    Fingerprint

    Dive into the research topics of 'The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B'. Together they form a unique fingerprint.

    Cite this