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Activation of G Proteins by Guanine Nucleotide Exchange Factors Relies on GTPase Activity
Open accessPublished version of a preprint
Abstract
G proteins are an important family of signalling molecules controlled by guanine nucleotide exchange and GTPase activity in what is commonly called an 'activation/inactivation cycle'. The molecular mechanism by which guanine nucleotide exchange factors (GEFs) catalyse the activation of monomeric G proteins is well-established, however the complete reversibility of this mechanism is often overlooked. Here, we use a theoretical approach to prove that GEFs are unable to positively control G protein systems at steady-state in the absence of GTPase activity. Instead, positive regulation of G proteins must be seen as a product of the competition between guanine nucleotide exchange and GTPase activity--emphasising a central role for GTPase activity beyond merely signal termination. We conclude that a more accurate description of the regulation of G proteins via these processes is as a 'balance/imbalance' mechanism. This result has implications for the understanding of intracellular signalling processes, and for experimental strategies that rely on modulating G protein systems.
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Cites
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“For G protein: GEF interactions, parameters measured for the Ran:RCC1:RanGAP1 system were used [25, 26]; concentrations of Ran and RCC1 were estimated from the PaxDB database [41] scaled by an estimate of the total concentration of proteins given by [42]; concentrations of nucleotides were taken from [43].”
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Metadata
- Authors
- Stanley, R. J., & Thomas, G. M. H.
- Affiliations
- University College London (GB)
- Corresponding author
- Thomas, Geraint M. H.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-03-17
- Volume
- 11
- Issue
- 3
- Pages
- e0151861
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4795700
- OpenAlex
- W2297611454
- Cited by
- 24
- References
- 4
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 1
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- British Heart Foundation (SP/08/004)
- 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 › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- G proteins, guanine nucleotide exchange factor, GTPase activity, G protein activation, G protein inactivation, signal termination, intracellular signaling, steady-state regulation
- MeSH terms
- Animals, Humans, Kinetics, Models, Biological, Transcriptional Activation, GTP-Binding Proteins, GTP Phosphohydrolases, Guanine Nucleotide Exchange Factors
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