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Cited by 65Protein Kinase Regulation and GTPase SignalingReceptor Mechanisms and SignalingCellular transport and secretion

Structural Insights into the Regulation Mechanism of Small GTPases by GEFs

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Toma-Fukai, Sachiko, Shimizu, Toshiyuki·2019·Molecules
DOI 10.3390/molecules24183308PMC PMC6767298
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Abstract

Small GTPases are key regulators of cellular events, and their dysfunction causes many types of cancer. They serve as molecular switches by cycling between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states. GTPases are deactivated by GTPase-activating proteins (GAPs) and are activated by guanine-nucleotide exchange factors (GEFs). The intrinsic GTP hydrolysis activity of small GTPases is generally low and is accelerated by GAPs. GEFs promote GDP dissociation from small GTPases to allow for GTP binding, which results in a conformational change of two highly flexible segments, called switch I and switch II, that enables binding of the gamma phosphate and allows small GTPases to interact with downstream effectors. For several decades, crystal structures of many GEFs and GAPs have been reported and have shown tremendous structural diversity. In this review, we focus on the latest structural studies of GEFs. Detailed pictures of the variety of GEF mechanisms at atomic resolution can provide insights into new approaches for drug discovery.

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  • GEFs catalyze the exchange of GDP for GTP, leading to conformational changes in switch I and switch II regions required for activation of small GTPases.

    “In response to extracellular stimuli emanating from cell surface receptors, guanine nucleotide exchange factors (GEFs) catalyze the exchange of GDP for GTP, leading to the conformational changes in the switch I and switch II regions required for activation of the small GTPases.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [14]

  • GAPs enhance the intrinsic GTPase activity of small GTPases, resulting in GTP hydrolysis to GDP and inorganic phosphate and inactivation of the GTPases.

    “Conversely, GTPase-activating proteins (GAPs) enhance the relatively slow intrinsic GTPase activity of the small GTPases, resulting in GTP hydrolysis to GDP and inorganic phosphate (Pi) and inactivation of the GTPases [5,14].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [14]

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Cited by

Sorted by citations

Authors
Toma-Fukai, S., & Shimizu, T.
Affiliations
  • Nara Institute of Science and Technology (JP)
  • The University of Tokyo (JP)
Corresponding author
  • Toma-Fukai, Sachiko
  • Shimizu, Toshiyuki
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2019-09-11
Volume
24
Issue
18
Pages
3308
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules24183308
PMC
PMC6767298
OpenAlex
W2972437640
Cited by
65
References
2
Citations by year
2026: 9 · 2025: 9 · 2024: 12 · 2023: 10 · 2022: 9 · 2021: 8 · 2020: 7 · 2017: 1
FWCI
0.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Naito Foundation
  • Uehara Memorial Foundation
  • Japan Society for the Promotion of Science (19H00976)
  • Core Research for Evolutional Science and Technology
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
small GTPases, guanine nucleotide exchange factor, GTPase-activating protein, GDP dissociation, GTP hydrolysis, GTPase activation, drug discovery
MeSH terms
Animals, Enzyme Activation, Humans, Phylogeny, Protein Folding, Monomeric GTP-Binding Proteins, Guanine Nucleotide Exchange Factors, Feedback, Physiological

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