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

Authors :
Dwight V. Nissley
Debanjan Goswami
Katie Powell
Yue Yang
John Columbus
Madeline Wheeler
Thomas J. Turbyville
Dominic Esposito
Vanessa Wall
Felice C. Lightstone
De Chen
Prabhakar R. Gudla
Megan Rigby
Frank McCormick
Suman Mukhopadhyay
William E. Burgan
Karen M. Worthy
Dhirendra K. Simanshu
Source :
eLife, eLife, Vol 9 (2020)
Publication Year :
2020
Publisher :
eScholarship, University of California, 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, 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.

Details

Database :
OpenAIRE
Journal :
eLife, eLife, Vol 9 (2020)
Accession number :
edsair.doi.dedup.....169e46d8abcdbbfc6691fbd11768e154