Activation of Rho GTPases by DOCK Exchange Factors Is Mediated by a Nucleotide Sensor
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Crystal Clear: Guanine nucleotide exchange factors stimulate exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and activate small guanosine triphosphatases (GTPases) required for the regulation of many biological processes. Yang et al. (p. 1398 ) provide a detailed picture of the complete catalytic cycle by which a guanine nucleotide exchange factor, DOCK9, activates the small GTPase, Cdc42. A small region of DOCK9 appears to sense whether GTP or GDP is bound to Cdc42 in a mechanism that is distinct from that observed for other GTPases.
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DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process otherwise too slow for rapid spatiotemporal control of cellular signaling.
“At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process that is otherwise too slow for rapid spatiotemporal control of cellular signaling.”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [35]
The DHR2 domain is responsible for GEF activity in a mechanism distinct from that of DH-containing GEFs.
“The DHR2 domain is responsible for GEF activity in a mechanism that is distinct from that of DH-containing GEFs (33, 34, 35).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [35]
DOCK-A and DOCK-B proteins activate RAC GTPases specifically, whereas the DOCK-D subfamily activates CDC42.
“Generally, DOCK-A and DOCK-B proteins activate the RAC GTPases specifically (35, 41), whereas the DOCK-D subfamily is responsible for activating CDC42.”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [35]
DOCK9 is a CDC42 GEF.
“DOCK9 is a CDC42 GEF (35).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [35]
DH GEFs elicit similar conformational changes in their GTPase substrates throughout the family.
“This is again in contrast to DH GEFs, which elicit similar conformational changes in their GTPases substrates throughout the family.”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [35]
The DOCK mechanism of eliciting GDP dissociation is distinct from the canonical DH-domain containing GEFs, where Mg2+ occlusion is typically accomplished by eliciting displacement of the GTPase switch 2 loop.
“The DOCK mechanism of eliciting GDP dissociation is distinct from the canonical DH-domain containing GEFs, where Mg2+ occlusion is typically accomplished by eliciting displacement of the GTPase switch 2 loop (35).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [35]
Pathogen proteins can have surfaces that resemble host protein surfaces, allowing them to mimic and compete with host protein interactions.
“Mechanistically, pathogen proteins can have surfaces which resemble those of the host, allowing them to mimic and compete with host protein interactions (Figure 3).”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [207]
Human-microbiome protein-protein interactions promote GTPase activation.
“Figure 3 Human–microbiome PPIs promote GTPase activation.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [207]
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- Authors
- Yang, J., Zhang, Z., Roe, S. M., Marshall, C. J., & Barford, D.
- Affiliations
- Institute of Cancer Research (GB)
- Corresponding author
- Barford, David
- Venue
- Science
- Published
- 2009-09-11
- Volume
- 325
- Issue
- 5946
- Pages
- 1398-1402
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2084566151
- Cited by
- 123
- References
- 28
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 5 · 2018: 2 · 2017: 2 · 2016: 6 · 2015: 13 · 2014: 6 · 2013: 12 · 2012: 9
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Licence
- cc-by
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research UK
- 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
- Rho GTPases, Cdc42, guanine nucleotide exchange factor, GDP release
- MeSH terms
- Amino Acid Sequence, Enzyme Activation, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Magnesium, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray, Catalytic Domain, Guanine Nucleotide Exchange Factors, cdc42 GTP-Binding Protein
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