Regulation of Small GTPases by GEFs, GAPs, and GDIs
Abstract
Small GTPases use GDP/GTP alternation to actuate a variety of functional switches that are pivotal for cell dynamics. The GTPase switch is turned on by GEFs, which stimulate dissociation of the tightly bound GDP, and turned off by GAPs, which accelerate the intrinsically sluggish hydrolysis of GTP. For Ras, Rho, and Rab GTPases, this switch incorporates a membrane/cytosol alternation regulated by GDIs and GDI-like proteins. The structures and core mechanisms of representative members of small GTPase regulators from most families have now been elucidated, illuminating their general traits combined with scores of unique features. Recent studies reveal that small GTPase regulators have themselves unexpectedly sophisticated regulatory mechanisms, by which they process cellular signals and build up specific cell responses. These mechanisms include multilayered autoinhibition with stepwise release, feedback loops mediated by the activated GTPase, feed-forward signaling flow between regulators and effectors, and a phosphorylation code for RhoGDIs. The flipside of these highly integrated functions is that they make small GTPase regulators susceptible to biochemical abnormalities that are directly correlated with diseases, notably a striking number of missense mutations in congenital diseases, and susceptible to bacterial mimics of GEFs, GAPs, and GDIs that take command of small GTPases in infections. This review presents an overview of the current knowledge of these many facets of small GTPase regulation.
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Ral and Rab GTPases cycle between GDP-bound inactive and GTP-bound active states.
“Similar to other small GTPases, Ral and Rab cycle between a guanosine diphosphate (GDP)–bound inactive state and a GTP-bound active state (10–12).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [12]
GEFs recognize GDP-bound small GTPases and accelerate GDP release, leading to GTP binding and activation.
“Guanine nucleotide exchange factors (GEFs) recognize the GDP-bound form of small GTPases and accelerate GDP release, leading to GTP binding and activation.”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [12]
GAPs recognize GTP-bound small GTPases and stimulate GTP hydrolysis, inactivating them.
“GTPase-activating proteins (GAPs), on the other hand, recognize the GTP-bound form of small GTPases and stimulate guanosine 5′-triphosphate (GTP) hydrolysis, inactivating the small GTPases (12).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [12]
Ralbp1 interacts with switches 1 and 2 of GTP-bound Rals, the same region recognized by RalGAPs.
“Ralbp1 interacts with switches 1 and 2 of GTP-bound Rals, the same region recognized by RalGAPs (12, 45, 60).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [12]
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- Authors
- Cherfils, J., & Zeghouf, M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Cherfils, Jacqueline
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2013-01
- Volume
- 93
- Issue
- 1
- Pages
- 269-309
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- OpenAlex
- W2069738597
- Cited by
- 1,245
- References
- 6
- Citations by year
- 2026: 78 · 2025: 95 · 2024: 90 · 2023: 95 · 2022: 97 · 2021: 92 · 2020: 85 · 2019: 91 · 2018: 99 · 2017: 107 · 2016: 93 · 2015: 87 · 2014: 93 · 2013: 41
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiological Reviews (publishedVersion)
- PubMed (publishedVersion)
- 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
- small GTPases, guanine nucleotide exchange factor, guanine nucleotide dissociation inhibitor, GTPase-activating protein, GDP/GTP exchange, Ras GTPase, Rho GTPases, Rab GTPases, RhoGDI, autoinhibition, feedback loops, feed-forward signaling, phosphorylation, missense mutations, congenital diseases, bacterial infection
- MeSH terms
- Allosteric Regulation, Animals, Enzyme Activation, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Hydrolysis, Models, Molecular, Protein Conformation, Structure-Activity Relationship, Signal Transduction, Catalytic Domain, Monomeric GTP-Binding Proteins, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, Guanine Nucleotide Dissociation Inhibitors
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