Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783504155966439424 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7060043 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT goswamidebanjan membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT chende membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT yangyue membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT gudlaprabhakarr membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT columbusjohn membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT worthykaren membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT rigbymegan membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT wheelermadeline membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT mukhopadhyaysuman membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT powellkatie membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT burganwilliam membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT wallvanessa membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT espositodominic membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT simanshudhirendrak membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT lightstonefelicec membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT nissleydwightv membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT mccormickfrank membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior AT turbyvillethomas membraneinteractionsoftheglobulardomainandthehypervariableregionofkras4bdefineitsuniquediffusionbehavior |