Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1
Abstract
The principal guanine nucleotide exchange factors for Rho family G proteins contain tandem Dbl-homology (DH) and pleckstrin-homology (PH) domains that catalyse nucleotide exchange and the activation of G proteins. Here we have determined the crystal structure of the DH and PH domains of the T-lymphoma invasion and metastasis factor 1 (Tiam1) protein in complex with its cognate Rho family G protein, Rac1. The two switch regions of Rac1 are stabilized in conformations that disrupt both magnesium binding and guanine nucleotide interaction. The resulting cleft in Rac1 is devoid of nucleotide and highly exposed to solvent. The PH domain of Tiam1 does not contact Rac1, and the position and orientation of the PH domain is markedly altered relative to the structure of the uncomplexed, GTPase-free DH/PH element from Sos1. The Tiam1/Rac1 structure highlights the interactions that catalyse nucleotide exchange on Rho family G proteins, and illustrates structural determinants dictating specificity between individual Rho family members and their associated Dbl-related guanine nucleotide exchange factors.
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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 [29]
Divergent 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 [29]
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 [29]
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Self-citation
- Authors
- Worthylake, D. K., Rossman, K. L., & Sondek, J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Venue
- Nature
- Published
- 2000-12-07
- Volume
- 408
- Issue
- 6813
- Pages
- 682-688
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1887383255
- Cited by
- 355
- References
- 42
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 11 · 2023: 2 · 2022: 8 · 2021: 6 · 2020: 16 · 2019: 6 · 2018: 11 · 2017: 6 · 2016: 9 · 2015: 13 · 2014: 7 · 2013: 16 · 2012: 16
- FWCI
- 7.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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 › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Rac1, Tiam1, guanine nucleotide exchange factor, Dbl homology domain, pleckstrin homology domain, nucleotide exchange, switch regions, magnesium binding, GTPase activation, protein complex structure, SOS1
- MeSH terms
- T-Lymphoma Invasion and Metastasis-inducing Protein 1, Animals, Binding Sites, Escherichia coli, Humans, Models, Molecular, Mutation, Proteins, Recombinant Fusion Proteins, Protein Structure, Tertiary, Crystallography, X-Ray, GTP Phosphohydrolases, Guanine Nucleotide Exchange Factors, rac1 GTP-Binding Protein, Macromolecular Substances, Mice
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