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Authors: 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
TITLE: Membrane Interactions of the Globular Domain and the Hypervariable Region of KRAS4b Define Its Unique Diffusion Behavior , eLife , 9 : e47654 , 2020
PUBLICATION DATE: 01-20-2020
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, the authors characterized 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, the authors used complementary experimental and molecular dynamics simulation approaches to reveal a detailed mechanism.
PROJECT: ADMIRRAL
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https://doi.org/10.7554/eLife.47654
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