Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane
Abstract
The small GTPase KRAS is localized at the plasma membrane where it functions as a molecular switch, coupling extracellular growth factor stimulation to intracellular signaling networks. In this process, KRAS recruits effectors, such as RAF kinase, to the plasma membrane where they are activated by a series of complex molecular steps. Defining the membrane-bound state of KRAS is fundamental to understanding the activation of RAF kinase and in evaluating novel therapeutic opportunities for the inhibition of oncogenic KRAS-mediated signaling. Additionally, we combined multiple biophysical measurements and computational methodologies to generate a consensus model for authentically processed, membrane-anchored KRAS. In contrast to the two membrane-proximal conformations previously reported, we identify a third significantly populated state using a combination of neutron reflectivity, fast photochemical oxidation of proteins (FPOP), and NMR. In this highly populated state, which we refer to as “membrane-distal” and estimate to comprise ~90% of the ensemble, the G-domain does not directly contact the membrane but is tethered via its C-terminal hypervariable region and carboxymethylated farnesyl moiety, as shown by FPOP. Subsequent interaction of the RAF1 RAS binding domain with KRAS does not significantly change G-domain configurations on the membrane but affects their relative populations. Overall, our results are consistentmore »
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- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1659370
- Alternate Identifier(s):
- OSTI ID: 1735440
- Grant/Contract Number:
- JDACS4C; AC02-06-CH11357; AC52-07NA27344; AC5206NA25396; AC05-00OR22725
- Resource Type:
- Published Article
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 117 Journal Issue: 39; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; KRAS; membrane; GTPase; RAF RBD; nuclear magnetic resonance; neutron reflectivity; fast photochemical oxidation of proteins
Citation Formats
Van, Que N., López, Cesar A., Tonelli, Marco, Taylor, Troy, Niu, Ben, Stanley, Christopher B., Bhowmik, Debsindhu, Tran, Timothy H., Frank, Peter H., Messing, Simon, Alexander, Patrick, Scott, Daniel, Ye, Xiaoying, Drew, Matt, Chertov, Oleg, Lösche, Mathias, Ramanathan, Arvind, Gross, Michael L., Hengartner, Nicolas W., Westler, William M., Markley, John L., Simanshu, Dhirendra K., Nissley, Dwight V., Gillette, William K., Esposito, Dominic, McCormick, Frank, Gnanakaran, S., Heinrich, Frank, and Stephen, Andrew G. Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane. United States: N. p., 2020.
Web. doi:10.1073/pnas.2006504117.
Van, Que N., López, Cesar A., Tonelli, Marco, Taylor, Troy, Niu, Ben, Stanley, Christopher B., Bhowmik, Debsindhu, Tran, Timothy H., Frank, Peter H., Messing, Simon, Alexander, Patrick, Scott, Daniel, Ye, Xiaoying, Drew, Matt, Chertov, Oleg, Lösche, Mathias, Ramanathan, Arvind, Gross, Michael L., Hengartner, Nicolas W., Westler, William M., Markley, John L., Simanshu, Dhirendra K., Nissley, Dwight V., Gillette, William K., Esposito, Dominic, McCormick, Frank, Gnanakaran, S., Heinrich, Frank, & Stephen, Andrew G. Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane. United States. https://doi.org/10.1073/pnas.2006504117
Van, Que N., López, Cesar A., Tonelli, Marco, Taylor, Troy, Niu, Ben, Stanley, Christopher B., Bhowmik, Debsindhu, Tran, Timothy H., Frank, Peter H., Messing, Simon, Alexander, Patrick, Scott, Daniel, Ye, Xiaoying, Drew, Matt, Chertov, Oleg, Lösche, Mathias, Ramanathan, Arvind, Gross, Michael L., Hengartner, Nicolas W., Westler, William M., Markley, John L., Simanshu, Dhirendra K., Nissley, Dwight V., Gillette, William K., Esposito, Dominic, McCormick, Frank, Gnanakaran, S., Heinrich, Frank, and Stephen, Andrew G. Thu .
"Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane". United States. https://doi.org/10.1073/pnas.2006504117.
@article{osti_1659370,
title = {Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane},
author = {Van, Que N. and López, Cesar A. and Tonelli, Marco and Taylor, Troy and Niu, Ben and Stanley, Christopher B. and Bhowmik, Debsindhu and Tran, Timothy H. and Frank, Peter H. and Messing, Simon and Alexander, Patrick and Scott, Daniel and Ye, Xiaoying and Drew, Matt and Chertov, Oleg and Lösche, Mathias and Ramanathan, Arvind and Gross, Michael L. and Hengartner, Nicolas W. and Westler, William M. and Markley, John L. and Simanshu, Dhirendra K. and Nissley, Dwight V. and Gillette, William K. and Esposito, Dominic and McCormick, Frank and Gnanakaran, S. and Heinrich, Frank and Stephen, Andrew G.},
abstractNote = {The small GTPase KRAS is localized at the plasma membrane where it functions as a molecular switch, coupling extracellular growth factor stimulation to intracellular signaling networks. In this process, KRAS recruits effectors, such as RAF kinase, to the plasma membrane where they are activated by a series of complex molecular steps. Defining the membrane-bound state of KRAS is fundamental to understanding the activation of RAF kinase and in evaluating novel therapeutic opportunities for the inhibition of oncogenic KRAS-mediated signaling. Additionally, we combined multiple biophysical measurements and computational methodologies to generate a consensus model for authentically processed, membrane-anchored KRAS. In contrast to the two membrane-proximal conformations previously reported, we identify a third significantly populated state using a combination of neutron reflectivity, fast photochemical oxidation of proteins (FPOP), and NMR. In this highly populated state, which we refer to as “membrane-distal” and estimate to comprise ~90% of the ensemble, the G-domain does not directly contact the membrane but is tethered via its C-terminal hypervariable region and carboxymethylated farnesyl moiety, as shown by FPOP. Subsequent interaction of the RAF1 RAS binding domain with KRAS does not significantly change G-domain configurations on the membrane but affects their relative populations. Overall, our results are consistent with a directional fly-casting mechanism for KRAS, in which the membrane-distal state of the G-domain can effectively recruit RAF kinase from the cytoplasm for activation at the membrane.},
doi = {10.1073/pnas.2006504117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 39,
volume = 117,
place = {United States},
year = {Thu Sep 10 00:00:00 EDT 2020},
month = {Thu Sep 10 00:00:00 EDT 2020}
}
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