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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.

SUBMITTER: Goswami D

PROVIDER: S-EPMC7060043 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Goswami Debanjan D Chen De Yang Yue Y Gudla Prabhakar R PR Columbus John J Worthy Karen K Rigby Megan M Wheeler Madeline M Mukhopadhyay Suman S Powell Katie K Burgan William W Wall Vanessa V Esposito Dominic D Simanshu Dhirendra K DK Lightstone Felice C FC Nissley Dwight V DV McCormick Frank F Turbyville Thomas T

eLife 20200120

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. ...[more]

PMID: 31958057

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

Publications

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

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