Structural basis for the selective activation of Rho GTPases by Dbl exchange factors
Abstract
Activation of Rho-family GTPases involves the removal of bound GDP and the subsequent loading of GTP, all catalyzed by guanine nucleotide exchange factors (GEFs) of the Dbl-family. Despite high sequence conservation among Rho GTPases, Dbl proteins possess a wide spectrum of discriminatory potentials for Rho-family members. To rationalize this specificity, we have determined crystal structures of the conserved, catalytic fragments (Dbl and pleckstrin homology domains) of the exchange factors intersectin and Dbs in complex with their cognate GTPases, Cdc42 and RhoA, respectively. Structure-based mutagenesis of intersectin and Dbs reveals the key determinants responsible for promoting exchange activity in Cdc42, Rac1 and RhoA. These findings provide critical insight into the structural features necessary for the proper pairing of Dbl-exchange factors with Rho GTPases and now allow for the detailed manipulation of signaling pathways mediated by these oncoproteins in vivo.
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Previous studies have revealed that DH domain GEFs discriminate between Rac and Cdc42 based on their β2 and β3 strands.
“Previous studies have revealed that DH domain GEFs discriminate between Rac and Cdc42 based on their 2 and 3 strands (45,46).”
From Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors (2008) · cites this paper as [45]
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 [45]
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.
“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 [45]
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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Margolis, S. S., Salogiannis, J., Lipton, D. M., Mandel-Brehm, C., Wills, Z. P., Mardinly, A. R., Hu, L., Greer, P. L., Bikoff, J. B., Ho, H.-Y. H., et al. (2010) · Cell · doi:10.1016/j.cell.2010.09.038 · Cited by 256 · see citing works
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
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
- Snyder, J. T., Worthylake, D. K., Rossman, K. L., Betts, L., Pruitt, W. M., Siderovski, D. P., Der, C. J., & Sondek, J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Sondek, John
- Venue
- Nature Structural Biology
- Published
- 2002-05-13
- Volume
- 9
- Issue
- 6
- Pages
- 468-475
- ISSN
- 1072-8368 (ISSN-L)
- OpenAlex
- W2153637044
- Cited by
- 209
- References
- 1
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 7 · 2021: 6 · 2020: 13 · 2019: 9 · 2018: 5 · 2017: 4 · 2016: 6 · 2015: 4 · 2014: 6 · 2013: 12 · 2012: 12
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Structural Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- Pew Charitable Trusts
- National Institutes of Health
- 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
- Rho GTPases, Cdc42, RhoA, Rac1, intersectin, DBS, pleckstrin homology domain, GTP loading, substrate specificity, crystal structure, structure-guided mutagenesis, GTPase signaling
- MeSH terms
- T-Lymphoma Invasion and Metastasis-inducing Protein 1, Amino Acid Sequence, Enzyme Activation, Guanosine Triphosphate, Humans, Models, Molecular, Molecular Sequence Data, Proteins, Proto-Oncogene Proteins, Structure-Activity Relationship, Substrate Specificity, Sequence Alignment, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray, Guanine Nucleotide Exchange Factors, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein
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