Individual Rate Constants for the Interaction of Ras Proteins with GTPase-Activating Proteins Determined by Fluorescence Spectroscopy
Abstract
Individual rate constants for the interaction of H-, K-, and N-Ras with GAP-334 and NF1-333 were determined using fluorescent derivatives of guanine nucleotides at the active site of the Ras proteins. Stopped-flow experiments with NF1-333 show a fast concentration-dependent initial phase corresponding to the binding reaction followed by a slower phase, which corresponds to the hydrolysis reaction. With Ras bound to the nonhydrolyzable analogue mant-GppNHp, only the concentration-dependent first phase was observed. The Ras x mant-GppNHp x NF1-333 complexes were also used to measure dissociation rate constants of the Ras-GAP complexes. Using GAP-334 as the catalyst, the concentration-dependent first phase was too fast to be measured by the stopped-flow method, but the subsequent chemical cleavage reaction occurred at a similar rate (5-10 s(-1)) to that seen with NF1-333. With both GAP-334 and NF1-333, after rapidly reaching the initial equilibrium, there was no further time-dependent change on mixing GAPs with Ras x mant-GppNHp. The results obtained provide new insights into the individual steps of the GAP-catalyzed GTPase reaction on Ras. They do not require the postulation of a rate-limiting step occurring before GTP hydrolysis.
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Wild-type RAS isoforms have weak intrinsic GTPase activity and can self-inactivate, while RAS-GAPs stimulate this activity dramatically, increasing it fivefold over the intrinsic rate.
“Wild-type RAS isoforms have intrinsic, albeit weak, hydrolytic (GTPase) activity and can, therefore, self-inactivate; however, RAS-GAPs stimulate this activity dramatically11–14. Indeed, the GAPs increase RAS GTPase activity fivefold relative to the intrinsic rate12.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [11]
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- Authors
- Ahmadian, M. R., Hoffmann, U., Goody, R. S., & Wittinghofer, A.
- Affiliations
- Max Planck Institute of Molecular Physiology (DE)
- Corresponding author
- Wittinghofer, Alfred
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1997-04-01
- Volume
- 36
- Issue
- 15
- Pages
- 4535-4541
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2029458736
- Cited by
- 141
- References
- 11
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 2 · 2013: 7 · 2012: 6
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- 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 › Biochemical and Molecular Research
- Keywords
- Ras proteins, GTPase-activating protein, H-Ras, KRAS, NRAS, GTP hydrolysis, dissociation rate constant, chemical cleavage, rate-determining step
- MeSH terms
- Catalysis, Drug Interactions, Enzyme Activation, Kinetics, Proteins, Spectrometry, Fluorescence, ras Proteins, GTP Phosphohydrolases, GTPase-Activating Proteins, ras GTPase-Activating Proteins, Neurofibromin 1
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