Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor
Open accessAbstract
The Dedicator Of CytoKinesis (DOCK) family of atypical guanine nucleotide exchange factors activates the Rho family GTPases Rac and/or Cdc42 through DOCK homology region 2 (DHR-2). Previous structural analyses of the DHR-2 domains of DOCK2 and DOCK9 have shown that they preferentially bind Rac1 and Cdc42, respectively; however, the molecular mechanism by which DHR-2 distinguishes between these GTPases is unclear. Here we report the crystal structure of the Cdc42-bound form of the DOCK7 DHR-2 domain showing dual specificity for Rac1 and Cdc42. The structure revealed increased substrate tolerance of DOCK7 at the interfaces with switch 1 and residue 56 of Cdc42. Furthermore, molecular dynamics simulations showed a closed-to-open conformational change in the DOCK7 DHR-2 domain between the Cdc42- and Rac1-bound states by lobe B displacement. Our results suggest that lobe B acts as a sensor for identifying different switch 1 conformations and explain how DOCK7 recognizes both Rac1 and Cdc42.
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DOCK10 appears to bind more than one GTPase, as evidenced by recent crystal structures in complex with CDC42 and RAC3.
“DOCK10 also appears to bind more than one GTPase as evidenced by recent crystal structures in complex with CDC42 and RAC3 (Table 1) (42, 43, 44).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [42]
DOCK7 has roles in axon formation, polarity, and myelination.
“It is highly expressed in the brain, where it has roles in axon formation, polarity, and myelination (42, 48, 104, 105).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [42]
DOCK7 is highly expressed in the brain.
“It is highly expressed in the brain, where it has roles in axon formation, polarity, and myelination (42, 48, 104, 105).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [42]
DOCK7 is a GEF for both RAC and CDC42 GTPases, with a slight catalytic preference for CDC42.
“DOCK7 exhibits dual specificity for RAC and CDC42 GTPases, with a slight catalytic preference for CDC42 (42).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [42]
DOCK10 is a GEF for both CDC42 and RAC GTPases.
“DOCK10 is a GEF for both CDC42 and RAC GTPases (42, 43, 44).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [42]
Cites
Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors
Kwofie, M. A., & Skowronski, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m705170200 · Cited by 36 · see citing works
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Thompson, A. P., Bitsina, C., Gray, J. L., von Delft, F., & Brennan, P. E. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100521 · Cited by 21 · see citing works
“It is highly expressed in the brain, where it has roles in axon formation, polarity, and myelination (42, 48, 104, 105).”
BackgroundMethodInfluential
- Authors
- Kukimoto-Niino, M., Tsuda, K., Ihara, K., Mishima-Tsumagari, C., Honda, K., Ohsawa, N., & Shirouzu, M.
- Affiliations
- RIKEN (JP)
- Corresponding author
- Shirouzu, Mikako
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 27
- Issue
- 5
- Pages
- 741-748.e3
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2921928087
- Cited by
- 25
- References
- 1
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 1
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency (15K06987)
- Drug Discovery and Life Science Research
- AMED (JP18am0101082)
- 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 › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- DOCK7, guanine nucleotide exchange factor, Rho GTPase activation, Rac1, Cdc42, substrate specificity, conformational change, crystal structure, molecular dynamics simulation
- MeSH terms
- Crystallization, Humans, Molecular Conformation, Substrate Specificity, Mutagenesis, Crystallography, X-Ray, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, Molecular Dynamics Simulation
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