Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior
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 region 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 dynamics simulation approaches to reveal a detailed mechanism.
- Authors:
-
[1];
[2];
[1]
- NCI 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, School of Medicine, University of California, San Francisco, San Francisco, United States
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1592514
- Alternate Identifier(s):
- OSTI ID: 1592515
- Grant/Contract Number:
- Joint Design of Advanced Computing Solutions for Cancer (JDACS4C)
- Resource Type:
- Published Article
- Journal Name:
- eLife
- Additional Journal Information:
- Journal Name: eLife Journal Volume: 9; Journal ID: ISSN 2050-084X
- Publisher:
- eLife Sciences Publications, Ltd.
- Country of Publication:
- United States
- Language:
- English
Citation Formats
Goswami, Debanjan, Chen, De, Yang, Yue, Gudla, Prabhakar R., Columbus, John, Worthy, Karen, Rigby, Megan, Wheeler, Madeline, Mukhopadhyay, Suman, Powell, Katie, Burgan, William, Wall, Vanessa, Esposito, Dominic, Simanshu, Dhirendra K., Lightstone, Felice C., Nissley, Dwight V., McCormick, Frank, and Turbyville, Thomas. Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior. United States: N. p., 2020.
Web. doi:10.7554/eLife.47654.
Goswami, Debanjan, Chen, De, Yang, Yue, Gudla, Prabhakar R., Columbus, John, Worthy, Karen, Rigby, Megan, Wheeler, Madeline, Mukhopadhyay, Suman, Powell, Katie, Burgan, William, Wall, Vanessa, Esposito, Dominic, Simanshu, Dhirendra K., Lightstone, Felice C., Nissley, Dwight V., McCormick, Frank, & Turbyville, Thomas. Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior. United States. doi:10.7554/eLife.47654.
Goswami, Debanjan, Chen, De, Yang, Yue, Gudla, Prabhakar R., Columbus, John, Worthy, Karen, Rigby, Megan, Wheeler, Madeline, Mukhopadhyay, Suman, Powell, Katie, Burgan, William, Wall, Vanessa, Esposito, Dominic, Simanshu, Dhirendra K., Lightstone, Felice C., Nissley, Dwight V., McCormick, Frank, and Turbyville, Thomas. Mon .
"Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior". United States. doi:10.7554/eLife.47654.
@article{osti_1592514,
title = {Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior},
author = {Goswami, Debanjan and Chen, De and Yang, Yue and Gudla, Prabhakar R. and Columbus, John and Worthy, Karen and Rigby, Megan and Wheeler, Madeline and Mukhopadhyay, Suman and Powell, Katie and Burgan, William and Wall, Vanessa and Esposito, Dominic and Simanshu, Dhirendra K. and Lightstone, Felice C. and Nissley, Dwight V. and McCormick, Frank and Turbyville, Thomas},
abstractNote = {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 region 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 dynamics simulation approaches to reveal a detailed mechanism.},
doi = {10.7554/eLife.47654},
journal = {eLife},
number = ,
volume = 9,
place = {United States},
year = {2020},
month = {1}
}
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DOI: 10.7554/eLife.47654
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