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

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060043/
https://www.ncbi.nlm.nih.gov/pubmed/31958057
http://dx.doi.org/10.7554/eLife.47654
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author 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
author_facet 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
author_sort Goswami, Debanjan
collection PubMed
description 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.
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spelling pubmed-70600432020-03-09 Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior 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 eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2020-01-20 /pmc/articles/PMC7060043/ /pubmed/31958057 http://dx.doi.org/10.7554/eLife.47654 Text en http://creativecommons.org/publicdomain/zero/1.0/ http://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (http://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Cancer Biology
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
title Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior
title_full Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior
title_fullStr Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior
title_full_unstemmed Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior
title_short Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior
title_sort membrane interactions of the globular domain and the hypervariable region of kras4b define its unique diffusion behavior
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060043/
https://www.ncbi.nlm.nih.gov/pubmed/31958057
http://dx.doi.org/10.7554/eLife.47654
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