Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior

Debanjan Goswami, De Chen, Yue Yang, Prabhakar Gudla, John Columbus, Karen Worthy, Megan Rigby, Madeline Wheeler, Suman Mukhopadhyay, Katie Powell, William Burgan, Vanessa Wall, Dominic Esposito, Dhirendra Simanshu, Felice Lightstone, Dwight V. Nissley, Frank McCormick, Thomas Turbyville

Research output: Contribution to journalArticle

Abstract

The RAS proteins are GTP-dependent switches that regulate signaling pathways and are frequently mutated in cancer. RAS proteins concentrate in the plasma membrane via lipid-tethers and hypervariable side-chain interactions in distinct nano-domains. However, little is known about RAS membrane dynamics and the details of RAS activation of downstream signaling. Here we characterize RAS in live human and mouse cells using single molecule tracking methods and estimate RAS mobility parameters. KRAS4b exhibits confined mobility with three diffusive states distinct from the other RAS isoforms (KRAS4a, NRAS, and HRAS); and although most of the amino acid differences between RAS isoforms lie within the hypervariable region, the additional confinement of KRAS4b is largely determined by the protein’s globular domain. To understand the altered mobility of an oncogenic KRAS4b we used complementary experimental and molecular dynamic simulation approaches to reveal a detailed mechanism.

Original languageEnglish (US)
Article numbere47654
JournaleLife
Volume9
DOIs
StatePublished - Jan 2020
Externally publishedYes

    Fingerprint

Keywords

  • Atomistic simulation
  • Cancer
  • RAS diffusion
  • Single molecule tracking

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Goswami, D., Chen, D., Yang, Y., Gudla, P., Columbus, J., Worthy, K., Rigby, M., Wheeler, M., Mukhopadhyay, S., Powell, K., Burgan, W., Wall, V., Esposito, D., Simanshu, D., Lightstone, F., Nissley, D. V., McCormick, F., & Turbyville, T. (2020). Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior. eLife, 9, [e47654]. https://doi.org/10.7554/eLife.47654