A crystallographic view of interactions between Dbs and Cdc42: PH domain‐assisted guanine nucleotide exchange
Open accessAbstract
Dbl-related oncoproteins are guanine nucleotide exchange factors (GEFs) specific for Rho guanosine triphosphatases (GTPases) and invariably possess tandem Dbl (DH) and pleckstrin homology (PH) domains. While it is known that the DH domain is the principal catalytic subunit, recent biochemical data indicate that for some Dbl-family proteins, such as Dbs and Trio, PH domains may cooperate with their associated DH domains in promoting guanine nucleotide exchange of Rho GTPases. In order to gain an understanding of the involvement of these PH domains in guanine nucleotide exchange, we have determined the crystal structure of a DH/PH fragment from Dbs in complex with Cdc42. The complex features the PH domain in a unique conformation distinct from the PH domains in the related structures of Sos1 and Tiam1.Rac1. Consequently, the Dbs PH domain participates with the DH domain in binding Cdc42, primarily through a set of interactions involving switch 2 of the GTPase. Comparative sequence analysis suggests that a subset of Dbl-family proteins will utilize their PH domains similarly to Dbs.
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The side chains of the critical amino acid residues, except for those at positions 51, are surface accessible and thus may contact the cognate CDM GEFs directly.
“The side chains of these critical amino acid residues, except for those at positions 51, are surface accessible and thus may contact the cognate CDM GEFs directly (28,29,45).”
From Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors (2008) · cites this paper as [28]
In “The interface between the PH domain of Dbs and Cdc42” (page unavailable), the paper describes direct contacts between Cdc42 side chains and the GEF Dbs, supporting the proposed contact mechanism. It does not identify the citing sentence’s critical residues, establish that their side chains are surface accessible, or discuss the exception at position 51 or cognate CDM GEFs. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDivergent amino acid residues in the β2-β3 regions of Rac and Cdc42 are the major determinants of specific interactions with DH-domain containing GEFs.
“These structural studies have also revealed that divergent amino acid residues in the 2-3 regions of Rac and Cdc42 are the major determinants of specific interactions with DH-domain containing GEFs (26 -29).”
From Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors (2008) · cites this paper as [28]
The Structural overview and the section on the Dbs–Cdc42 interface describe contacts between Rho GTPases and DH-domain GEFs, including a comparison with Tiam1–Rac1. They do not identify divergent residues in the β2–β3 regions of Rac and Cdc42 as the major determinants of interaction specificity; the Structural overview instead notes a DH-domain region implicated in binding specificity. Page numbers were not available in our copy. (LLM, conf=0.81)
Experimental — accuracy not yet measuredCrystal structures of DH domain GEFs such as Tiam1, ITSN1, and Dbs in complex with their cognate GTPases show that positions 27 and 30 of the Rho GTPases remain accessible in the complexes.
“Also, the crystal structures of DH domain GEFs such as Tiam1, ITSN1, and Dbs in complex with their cognate GTPases show that positions 27 and 30 of the Rho GTPases remain accessible in the complexes (28,29,45).”
From Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors (2008) · cites this paper as [28]
The Structural overview (page unavailable) describes the Dbs–Cdc42 structure and compares it with Tiam1–Rac1. It says the nucleotide-binding pocket is exposed to solvent, but explicitly excludes the switch regions from that description; positions 27 and 30 lie within switch 1. Our copy therefore does not establish that those specific positions remain accessible, and it does not discuss an ITSN1 complex. (LLM, conf=0.82)
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Cites
Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1
Worthylake, D. K., Rossman, K. L., & Sondek, J. (2000) · Nature · doi:10.1038/35047014 · Cited by 355 · see citing works
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Structural insights into host GTPase isoform selection by a family of bacterial GEF mimics
Huang, Z., Sutton, S. E., Wallenfang, A. J., Orchard, R. C., Wu, X., Feng, Y., Chai, J., & Alto, N. M. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1647 · Cited by 139 · see citing works
Structural basis for the reversible activation of a Rho protein by the bacterial toxin SopE
Buchwald, G., Friebel, A., Galán, J. E., Hardt, W., Wittinghofer, A., & Scheffzek, K. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf329 · Cited by 135 · see citing works
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
- Authors
- Rossman, K. L., Worthylake, D. K., Snyder, J. T., Siderovski, D. P., Campbell, S. L., & Sondek, J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Sondek, John
- Venue
- The EMBO Journal
- Published
- 2002-03-15
- Volume
- 21
- Issue
- 6
- Pages
- 1315-1326
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC125919
- OpenAlex
- W2085082922
- Cited by
- 222
- References
- 1
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 7 · 2019: 8 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 5 · 2012: 12
- FWCI
- 7.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Wellcome Trust
- National Institutes of Health (5r01gm062299-08)
- National Institute of General Medical Sciences (R01-GM062299, GM62299)
- 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 › Protein Structure and Dynamics
- Keywords
- DBS, Cdc42, guanine nucleotide exchange, pleckstrin homology domain, Dbl homology domain, Rho GTPases, trios, SOS1, Tiam1, Rac1
- MeSH terms
- Amino Acid Sequence, Animals, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Crystallography, X-Ray, Guanine Nucleotide Exchange Factors, cdc42 GTP-Binding Protein, Mice, Rho Guanine Nucleotide Exchange Factors
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