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

Author:

Goswami,Debanjan [ORCID]

Chen,De

Yang, Yue

Gudla, Prabhakar R

Columbus,John

Worthy,Karen

Rigby, Megan

Wheeler,Maddie

Mukhopadhyay,Suman

Powell,Katie

Burgan, William

Wall,Vanessa

Esposito,Dom

Simanshu,Dhirendra

Lightstone, Felice C [ORCID]

Nissley,Dwight

McCormick, Frank

Turbyville,Tommy [ORCID]
Author Address

RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, United States., Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, United States., UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States.,

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 39;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.

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Author Address