Oncogenic and RASopathy-associated K-RAS mutations relieve membrane-dependent occlusion of the effector-binding site
Open accessAbstract
Significance: KRAS (Kirsten rat sarcoma viral oncogene homolog) is frequently mutated in pancreatic, colon, and lung tumors, which predicts poor clinical outcome, whereas germ-line mutations are associated with developmental disorders, including Noonan syndrome. Although K-RAS is an attractive anticancer target, no clinically successful inhibitors are available. Most disease-associated mutations elevate the activated GTP-bound form of KRAS; however, some remain unexplained. KRAS signals from cellular membranes; however, our studies revealed that its association with the membrane surface sequesters its binding site for effector proteins, hampering signaling. Some disease-associated KRAS mutations disrupt this autoinhibition, identifying a new gain-of-function mechanism and explaining how certain Noonan syndrome mutations activate K-RAS signaling. Importantly, these findings open new avenues for therapeutic strategies to target oncogenic K-RAS through stabilizing autoinhibitory interactions with the membrane.
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RAS mutants were once thought to be locked in the GTP-bound on state and undruggable, but detailed structural and biochemical analyses have revealed differences among RAS mutants in GTPase activity, GDP-GTP exchange and effector binding.
“RAS mutants were once viewed as being ‘locked’ in the GTP-bound ‘on’ state, impervious to GAP-stimulated or intrinsic GTP hydrolysis, and hence undruggable. However, detailed structural and biochemical analyses of various RAS mutants associated with cancer and ‘RASopathies’”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [47]
GDP-bound KRAS drives the protein in the 'exposed' configuration on the membrane, where the α4-helix is located in close proximity to the membrane.
“They observed that the GDP-bound KRAS drives the protein in the “exposed” configuration on the membrane, where the α4-helix is located in close proximity to the membrane (PDB ID: 2MSC).”
This observation is in agreement with the experimental results by Mazhab-Jafari et al.
“This observation is in agreement with the experimental results by Mazhab-Jafari et al. [23].”
The altered dynamics may cause a conformational change of KRAS on the membrane, resulting in occluded conformation from a specific effector, alter dimer formation, or affect KRAS nanoclustering.
“The altered dynamics may cause a conformational change of KRAS on the membrane, resulting in occluded conformation from a specific effector [23], alter the dimer formation [64], or affect KRAS nanoclustering [65].”
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Cites
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,720 · see citing works
CHARMM‐GUI: A web‐based graphical user interface for CHARMM
Jo, S., Kim, T., Iyer, V. G., & Im, W. (2008) · Journal of Computational Chemistry · doi:10.1002/jcc.20945 · Cited by 9,284 · see citing works
HADDOCK: A Protein−Protein Docking Approach Based on Biochemical or Biophysical Information
Dominguez, C., Boelens, R., & Bonvin, A. M. J. J. (2003) · Journal of the American Chemical Society · doi:10.1021/ja026939x · Cited by 3,187 · see citing works
Peptide Folding: When Simulation Meets Experiment
Daura, X., Gademann, K., Jaun, B., Seebàch, D., van Gunsteren, W. F., & Mark, A. E. (1999) · Angewandte Chemie International Edition · doi:10.1002/(sici)1521-3773(19990115)38:1/2 · Cited by 2,059 · see citing works
Frequent pathway mutations of splicing machinery in myelodysplasia
Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R., Sato, Y., Sato-Otsubo, A., Kon, A., Nagasaki, M., et al. (2011) · Nature · doi:10.1038/nature10496 · Cited by 2,029 · see citing works
An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0
Malde, A. K., Zuo, L., Breeze, M., Stroet, M., Poger, D., Nair, P. C., Oostenbrink, C., & Mark, A. E. (2011) · Journal of Chemical Theory and Computation · doi:10.1021/ct200196m · Cited by 1,877 · see citing works
RAS oncogenes: weaving a tumorigenic web
Pylayeva-Gupta, Y., Grabocka, E., & Bar-Sagi, D. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3106 · Cited by 1,789 · see citing works
Stephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.017 · Cited by 795 · see citing works
Germline KRAS mutations cause Noonan syndrome
Schubbert, S., Zenker, M., Rowe, S. L., Böll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., et al. (2006) · Nature Genetics · doi:10.1038/ng1748 · Cited by 730 · see citing works
Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome
Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cavé, H., Verloès, A., Okamoto, N., Hennekam, R. C. M., Gillessen‐Kaesbach, G., Wieczorek, D., et al. (2006) · Nature Genetics · doi:10.1038/ng1749 · Cited by 599 · see citing works
HADDOCK versus HADDOCK: New features and performance of HADDOCK2.0 on the CAPRI targets
de Vries, S. D., van Dijk, A. V., Krzeminski, M., van Dijk, M. V., Thureau, A., Hsu, V. L., Wassenaar, T., & Bonvin, A. M. J. J. (2007) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.21723 · Cited by 583 · see citing works
Regulating the regulator: post-translational modification of RAS
Ahearn, I. M., Haigis, K. M., Bar‐Sagi, D., & Philips, M. R. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3255 · Cited by 560 · see citing works
Im, W., Beglov, D. B., & Roux, B. (1998) · Computer Physics Communications · doi:10.1016/s0010-4655(98)00016-2 · Cited by 541 · see citing works
Tugarinov, V., Kanelis, V., & Kay, L. (2006) · Nature Protocols · doi:10.1038/nprot.2006.101 · Cited by 506 · see citing works
Self-citationPlasma membrane nanoswitches generate high-fidelity Ras signal transduction
Tian, T., Harding, A. S., Inder, K. L., Plowman, S. J., Parton, R. G., & Hancock, J. F. (2007) · Nature Cell Biology · doi:10.1038/ncb1615 · Cited by 407 · see citing works
Protein NMR Using Paramagnetic Ions
Otting, G. (2010) · Annual Review of Biophysics · doi:10.1146/annurev.biophys.093008.131321 · Cited by 389 · see citing works
The exomes of the NCI-60 panel: a genomic resource for cancer biology and systems pharmacology
Abaan, O. D., Polley, E. C., Davis, S. R., Zhu, Y. J., Bilke, S., Walker, R. L., Pineda, M., Gindin, Y., Jiang, Y., Reinhold, W. C., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3342 · Cited by 288 · see citing works
Nava, C., Hanna, N., Michot, C., Pereira, S., Pouvreau, N., Niihori, T., Aoki, Y., Matsubara, Y., Arveiler, B., Lacombe, D., et al. (2007) · Journal of Medical Genetics · doi:10.1136/jmg.2007.050450 · Cited by 256 · see citing works
PBEQ-Solver for online visualization of electrostatic potential of biomolecules
Jo, S., Vargyas, M., Vasko-Szedlar, J., Roux, B., & Im, W. (2008) · Nucleic Acids Res. · doi:10.1093/nar/gkn314 · Cited by 251 · see citing works
Geyer, M., Schweins, T., Herrmann, C., Prisner, T. F., Wittinghofer, A., & Kalbitzer, H. R. (1996) · Biochemistry · doi:10.1021/bi952858k · Cited by 227 · see citing works
Carta, C., Pantaleoni, F., Bocchinfuso, G., Stella, L., Vasta, I., Sárközy, A., Digilio, C., Palleschi, A., Pizzuti, A., Grammatico, P., et al. (2006) · The American Journal of Human Genetics · doi:10.1086/504394 · Cited by 225 · see citing works
Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD
Fetics, S., Guterres, H., Kearney, B. M., Buhrman, G., Ma, B., Nussinov, R., & Mattos, C. (2015) · Structure · doi:10.1016/j.str.2014.12.017 · Cited by 225 · see citing works
Ras membrane orientation and nanodomain localization generate isoform diversity
Abankwa, D., Gorfe, A. A., Inder, K. L., & Hancock, J. F. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903907107 · Cited by 223 · see citing works
Schulz, T. A., Choi, M., Raychaudhuri, S., Mears, J. A., Ghirlando, R., Hinshaw, J. E., & Prinz, W. A. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200905007 · Cited by 221 · see citing works
Gorfe, A. A., Hanzal‐Bayer, M., Abankwa, D., Hancock, J. F., & McCammon, J. A. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm061053f · Cited by 209 · see citing works
Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations
Zenker, M., Lehmann, K., Schulz, A., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiß‐Nachtsheim, M., Meinecke, P., Morlot, S., et al. (2006) · Journal of Medical Genetics · doi:10.1136/jmg.2006.046300 · Cited by 202 · see citing works
A novel switch region regulates H‐ras membrane orientation and signal output
Abankwa, D., Hanzal‐Bayer, M., Ariotti, N., Plowman, S. J., Gorfe, A. A., Parton, R. G., McCammon, J. A., & Hancock, J. F. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.10 · Cited by 199 · see citing works
Grant, B. J., Gorfe, A. A., & McCammon, J. A. (2009) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000325 · Cited by 182 · see citing works
Influence of Cholesterol and Water Content on Phospholipid Lateral Diffusion in Bilayers
Filippov, A. V., Orädd, G., & Lindblom, G. (2003) · Langmuir · doi:10.1021/la034222x · Cited by 161 · see citing works
Gremer, L., Merbitz-Zahradnik, T., Dvorsky, R., Cirstea, I. C., Kratz, C. P., Zenker, M., Wittinghofer, A., & Ahmadian, M. R. (2011) · Human Mutation · doi:10.1002/humu.21377 · Cited by 158 · see citing works
Membrane-Mediated Induction and Sorting of K-Ras Microdomain Signaling Platforms
Weise, K., Kapoor, S., Denter, C., Nikolaus, J., Opitz, N., Koch, S., Triola, G., Herrmann, A., Waldmann, H., & Winter, R. (2010) · Journal of the American Chemical Society · doi:10.1021/ja107532q · Cited by 143 · see citing works
BRAF and KRAS mutations in stomach cancer
Lee, S. H., Lee, J. W., Soung, Y. H., Kim, H. S., Park, W. S., Kim, S. Y., Lee, J., Park, J. Y., Cho, Y. G., Kim, C. J., et al. (2003) · Oncogene · doi:10.1038/sj.onc.1206749 · Cited by 137 · see citing works
Membrane-Mediated Induction and Sorting of K-Ras Microdomain Signaling Platforms
Weise, K., Kapoor, S., Denter, C., Nikolaus, J., Opitz, N., Koch, S., Triola, G., Herrmann, A., Waldmann, H., & Winter, R. (2011) · Biophysical Journal · doi:10.1016/j.bpj.2010.12.689 · Cited by 112 · see citing works
Electrostatic Interactions Positively Regulate K-Ras Nanocluster Formation and Function
Plowman, S. J., Ariotti, N., Goodall, A., Parton, R. G., & Hancock, J. F. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00050-08 · Cited by 108 · see citing works
Araki, M., Shima, F., Yoshikawa, Y., Muraoka, S., Ijiri, Y., Nagahara, Y., Shirono, T., Kataoka, T., & Tamura, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.227074 · Cited by 105 · see citing works
Biochemical and Functional Characterization of Germ Line KRAS Mutations
Schubbert, S., Bollag, G. E., Lyubynska, N., Nguyen, H. T., Kratz, C. P., Zenker, M., Niemeyer, C. M., Molven, A., & Shannon, K. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00965-07 · Cited by 99 · see citing works
Kleywegt, G. J., Henrick, K., Dodson, E. J., et al. (2003) · Structure · doi:10.1016/s0969-2126(03)00186-2 · Cited by 88 · see citing works
Spoerner, M., Wittinghofer, A., & Kalbitzer, H. R. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.11.020 · Cited by 70 · see citing works
Mazhab‐Jafari, M. T., Marshall, C. B., Stathopulos, P. B., Kobashigawa, Y., Stambolic, V., Kay, L. E., Inagaki, F., & Ikura, M. (2013) · Journal of the American Chemical Society · doi:10.1021/ja312508w · Cited by 69 · see citing works
Self-citationKapoor, S., Weise, K., Erlkamp, M., Triola, G., Waldmann, H., & Winter, R. (2012) · European Biophysics Journal · doi:10.1007/s00249-012-0841-5 · Cited by 67 · see citing works
The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain
Parker, J. A., & Mattos, C. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0535 · Cited by 61 · see citing works
Advances in NMR structures of integral membrane proteins
Maslennikov, I., & Choe, S. (2013) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2013.05.002 · Cited by 47 · see citing works
Rotational and Translational Dynamics of Ras Proteins upon Binding to Model Membrane Systems
Werkmüller, A., Triola, G., Waldmann, H., & Winter, R. (2013) · ChemPhysChem · doi:10.1002/cphc.201300617 · Cited by 22 · see citing works
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- Authors
- Mazhab-Jafari, M. T., Marshall, C. B., Smith, M. J., Gasmi-Seabrook, G. M. C., Stathopulos, P. B., Inagaki, F., Kay, L. E., Neel, B. G., & Ikura, M.
- Affiliations
- Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada M5G 2M9;
- University of Toronto (CA)
- Hokkaido University (JP)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-05-04
- Volume
- 112
- Issue
- 21
- Pages
- 6625-6630
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4450377
- OpenAlex
- W1918986430
- Cited by
- 220
- References
- 43
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 9 · 2023: 18 · 2022: 21 · 2021: 21 · 2020: 35 · 2019: 22 · 2018: 22 · 2017: 28 · 2016: 16 · 2015: 7
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Society (14014)
- Princess Margaret Cancer Foundation (N/A)
- Canadian Cancer Society Research Institute (703209)
- Canada Research Chairs (N/A)
- Canada Foundation for Innovation (N/A)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- K-Ras4B, KRAS mutation, RASopathies, Noonan syndrome, Ras-binding domain, membrane association, autoinhibition, ARAF, RalGDS, G12D mutation, lipid bilayers, nanodiscs, conformational states, electrostatic interactions, oncogenic Ras, anticancer drug targets
- MeSH terms
- Amino Acid Sequence, Binding Sites, Humans, Lipid Bilayers, Models, Molecular, Molecular Sequence Data, Mutation, Protein Conformation, Genes, ras, Signal Transduction, Proto-Oncogene Proteins p21(ras), Sequence Homology, Amino Acid, Nuclear Magnetic Resonance, Biomolecular, ral Guanine Nucleotide Exchange Factor, Protein Interaction Domains and Motifs, Static Electricity, Molecular Dynamics Simulation
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