The DOI matches its Crossref record; 83 of the 84 references it cites were found in a registry or an index.
The small GTPases K-Ras, N-Ras, and H-Ras have distinct biochemical properties determined by allosteric effects
Open accessAbstract
H-Ras, K-Ras, and N-Ras are small GTPases that are important in the control of cell proliferation, differentiation, and survival, and their mutants occur frequently in human cancers. The G-domain, which catalyzes GTP hydrolysis and mediates downstream signaling, is 95% conserved between the Ras isoforms. Because of their very high sequence identity, biochemical studies done on H-Ras have been considered representative of all three Ras proteins. We show here that this is not a valid assumption. Using enzyme kinetic assays under identical conditions, we observed clear differences between the three isoforms in intrinsic catalysis of GTP by Ras in the absence and presence of the Ras-binding domain (RBD) of the c-Raf kinase protein (Raf-RBD). Given their identical active sites, isoform G-domain differences must be allosteric in origin, due to remote isoform-specific residues that affect conformational states. We present the crystal structure of N-Ras bound to a GTP analogue and interpret the kinetic data in terms of structural features specific for H-, K-, and N-Ras.
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“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 [45]
In the citing paper
“At the cellular level, the isoform specificity to effector proteins is primarily determined via membrane interactions [24], but the differences among RAS isoforms’ absolute effector protein binding affinities rise from allosteric effects [25].”
Citations
Cites
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“Molecular replacement and structure refinement were performed using the PHENIX suite of programs (81) with the H-Ras-GppNHp coordinates with PDB code 1CTQ used as the initial phasing model.”
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PHENIX: a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkòczi, G., Chen, V. B., Davis, I., Echols, N., Headd, J. J., Hung, L., Kapral, G. J., Grosse‐Kunstleve, R. W., et al. (2012) · International Tables for Crystallography · doi:10.1107/97809553602060000865 · Cited by 7,334
Nonlinear Regression Analysis and Its Applications
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The GTPase superfamily: conserved structure and molecular mechanism
Bourne, H. R., Sanders, D. A., & McCormick, F. (1991) · Nature · doi:10.1038/349117a0 · Cited by 3,392 · cited 8×
“The fact that Glu-143 links switch I to helix 5 residues, coupled with its interaction with Arg-123 in loop 8 as part of stabilizing the SAK residues at the nucleotide-binding site, explains the strictly conserved nature of Glu-143 across all GTPases.”
BackgroundInfluentialFundamentals of Enzyme Kinetics
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A Comprehensive Survey of Ras Mutations in Cancer
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“It is likely that localization and other large-scale biological contexts play a significant role in the selection of particular mutations in the Ras isoforms associated with specific cancers (76), but it is now clear that conformational states at the active site are affected by sequence at the molecular level in a glo…”
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The Frequency of Ras Mutations in Cancer
Prior, I. A., Hood, F. E., & Hartley, J. L. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3682 · Cited by 1,130
“Isoformspecific signaling is thought to be mediated by differential intracellular localisation that favors preferential coupling to specific effector pathways (4, 22, 23), and by distinct biochemical properties imparted by allosteric lobe sequence variations between each isoform (24).”
BackgroundMolecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
Salo‐Ahen, O. M. H., Alanko, I., Bhadane, R. N., Bonvin, A. M. J. J., Honorato, R. V., Hossain, S., Juffer, A. H., Kabedev, A., Lahtela-Kakkonen, M. K., Larsen, A. S., et al. (2020) · Processes · doi:10.3390/pr9010071 · Cited by 732
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549
The current understanding of KRAS protein structure and dynamics
Pantsar, T. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.12.004 · Cited by 304
“Since, it has been confirmed that the different isoforms exhibit distinct biochemical profiles [91].”
BackgroundSHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
Fedele, C., Li, S., Teng, K. W., Foster, C. J. R., Peng, D., Ran, H., Mita, P., Geer, M. J., Hattori, T., Koide, A., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201414 · Cited by 265
“” More recent analyses revealed subtle but key differences between RAS mutants in intrinsic and residual GAP-catalyzed GTPase activity, intrinsic and SOS-stimulated exchange, and effector binding (Bandaru et al., 2017; Gremer et al., 2011; Hunter et al., 2015; Johnson et al., 2017; Mazhab-Jafari et al., 2015; Smith an…”
Background
Metadata
- Authors
- Johnson, C. W., Reid, D., Parker, J. A., Salter, S., Knihtila, R., Kuzmic, P., & Mattos, C.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Mattos, Carla
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 292
- Issue
- 31
- Pages
- 12981-12993
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5546037
- OpenAlex
- W2717068414
- Cited by
- 133
- References
- 84
- Citations by year
- 2026: 12 · 2025: 7 · 2024: 15 · 2023: 10 · 2022: 20 · 2021: 18 · 2020: 14 · 2019: 20 · 2018: 12 · 2017: 5
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (1517295)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Ras GTPase, KRAS, NRAS, H-Ras, Ras isoforms, allosteric regulation, GTP hydrolysis, enzyme kinetics, Ras-binding domain
- MeSH terms
- Allosteric Regulation, Allosteric Site, Enzyme Stability, Guanosine Triphosphate, Humans, Isoenzymes, Ligands, Membrane Proteins, Models, Molecular, Peptide Fragments, Protein Conformation, Recombinant Proteins, Dinucleoside Phosphates, Proto-Oncogene Proteins p21(ras), Point Mutation, Crystallography, X-Ray, Proto-Oncogene Proteins c-raf, Amino Acid Substitution, Catalytic Domain, GTP Phosphohydrolases, Protein Interaction Domains and Motifs, Biocatalysis
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