Molecular basis for Rac1 recognition by guanine nucleotide exchange factors.
Abstract
Rho GTPases are activated by a family of guanine nucleotide exchange factors (GEFs) known as Dbl family proteins. The structural basis for how GEFs recognize and activate Rho GTPases is presently ill defined. Here, we utilized the crystal structure of the DH/PH domains of the Rac-specific GEF Tiam1 in complex with Rac1 to determine the structural elements of Rac1 that regulate the specificity of this interaction. We show that residues in the Rac1 beta2-beta3 region are critical for Tiam1 recognition. Additionally, we determined that a single Rac1-to-Cdc42 mutation (W56F) was sufficient to abolish Rac1 sensitivity to Tiam1 and allow recognition by the Cdc42-specific DH/PH domains of Intersectin while not impairing Rac1 downstream activities. Our findings identified unique GEF specificity determinants in Rac1 and provide important insights into the mechanism of DH/PH selection of GTPase targets.
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Previous studies demonstrated that DH domain GEFs distinguish between Rac and Cdc42 mainly via an aromatic residue at position 56.
“For example, previous studies demonstrated that the DH domain GEFs distinguish between Rac and Cdc42 mainly via an aromatic residue at position 56 (47,48).”
From Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors (2008) · cites this paper as [48]
A Rac-to-Cdc42 substitution of tryptophan at position 56 of Rac1 with phenylalanine (W56F) allows Rac1-(W56F) to be specifically activated by the otherwise Cdc42-specific DH domain GEF ITSN1, but not the Rac-specific DH domain GEF Tiam1.
“This is best illustrated by the observation that a Rac-to-Cdc42 substitution of the tryptophan residue at position 56 of Rac1 with phenylalanine (W56F) allows Rac1-(W56F) to be specifically activated by the otherwise Cdc42specific DH domain GEF ITSN1, but not the Rac-specific DH domain GEF Tiam1 (48).”
From Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors (2008) · cites this paper as [48]
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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Shutes, A., Onesto, C., Picard, V., Leblond, B., Schweighoffer, F., & Der, C. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703571200 · Cited by 336 · see citing works
Self-citationStructural 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
- Karnoub, A. E., Worthylake, D. K., Rossman, K. L., Pruitt, W. M., Campbell, S. L., Sondek, J., & Der, C. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Channing J. Der
- Venue
- Nature Structural Biology
- Published
- 2001-10-29
- Volume
- 8
- Issue
- 12
- Pages
- 1037-1041
- ISSN
- 1072-8368 (ISSN-L)
- OpenAlex
- W1500337621
- Cited by
- 93
- References
- 1
- Citations by year
- 2024: 2 · 2021: 1 · 2020: 6 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 6
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Structural Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- Rac1, guanine nucleotide exchange factor, Tiam1, Rho GTPase activation, Cdc42, intersectin, protein-protein interaction
- MeSH terms
- T-Lymphoma Invasion and Metastasis-inducing Protein 1, Animals, Binding Sites, Carrier Proteins, Cell Transformation, Neoplastic, Enzyme Activation, Humans, Ligands, Models, Molecular, Mutation, Protein Binding, Proteins, Recombinant Fusion Proteins, Substrate Specificity, Signal Transduction, Mutagenesis, Site-Directed, 3T3 Cells, Protein Structure, Tertiary, Amino Acid Substitution, Guanine Nucleotide Exchange Factors, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, Protein Interaction Mapping, Adaptor Proteins, Vesicular Transport, Mice
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