Structural basis for the selective activation of Rho GTPases by Dbl exchange factors
@article{Snyder2002StructuralBF, title={Structural basis for the selective activation of Rho GTPases by Dbl exchange factors}, author={Jason T. Snyder and David K. Worthylake and Kent L. Rossman and Laurie Betts and Wendy M. Pruitt and D. Siderovski and Channing J. Der and John Sondek}, journal={Nature Structural Biology}, year={2002}, volume={9}, pages={468-475} }
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…
218 Citations
Functional Analysis of Cdc42 Residues Required for Guanine Nucleotide Exchange*
- Biology, ChemistryThe Journal of Biological Chemistry
- 2002
Guanine nucleotide exchange factors (GEFs) directly engage small GTPases to facilitate the exchange of bound GDP for GTP, leading to GTPase activation. Several recent crystal structures of GEFs in…
Structural Determinants of RhoA Binding and Nucleotide Exchange in Leukemia-associated Rho Guanine-Nucleotide Exchange Factor*
- Biology, ChemistryJournal of Biological Chemistry
- 2004
It is shown that full nucleotide exchange activity requires a novel N-terminal extension on the DH domain that is predicted to exist in a broader family of RhoGEFs that includes p115-RhoGEF, Lbc, Lfc, Net1, and Xpln, and regions within the LARG PH domain that contribute to its ability to facilitate nucleotide Exchange in vitro.
Critical Role of the Pleckstrin Homology Domain in Dbs Signaling and Growth Regulation*
- Biology, ChemistryJournal of Biological Chemistry
- 2003
It is suggested that the PH domain of Dbs facilitates two distinct roles in the regulation of DH domain function, one critical for GTPase association and activation in vitro and onecritical for phosphoinositide binding and GTP enzyme interaction in vivo, that together promote Dbs association with membranes.
Multifunctional Roles for the PH Domain of Dbs in Regulating Rho GTPase Activation*
- BiologyThe Journal of Biological Chemistry
- 2003
The data suggest that binding of phosphoinositides to the PH domain within the context of membrane surfaces may direct orientations or conformations of the linked DH and PH domains to regulate GTPases activation.
The Molecular Basis of RhoA Specificity in the Guanine Nucleotide Exchange Factor PDZ-RhoGEF*
- Biology, ChemistryJournal of Biological Chemistry
- 2006
This work conducts extensive mutational and functional studies of the molecular basis of the RhoA selectivity in PDZ-RhoGEF and finds that selectivity for RHoA versus Cdc42 is defined by a small number of interactions.
The DH and PH domains of Trio coordinately engage Rho GTPases for their efficient activation.
- Biology, ChemistryJournal of molecular biology
- 2007
Mechanisms of Guanine Nucleotide Exchange and Rac-mediated Signaling Revealed by a Dominant Negative Trio Mutant*
- Biology, ChemistryJournal of Biological Chemistry
- 2004
A conserved pair of amino acid residues of the Trio-Rac interaction are identified that are likely to be essential to the GEF catalysis of Rho family GTPases and it is demonstrated that a dominant negative mutant derived from a Rho GTPase regulator constitutes a new generation of specific inhibitors of RHo G TPase signaling pathways.
Recognition and activation of Rho GTPases by Vav1 and Vav2 guanine nucleotide exchange factors.
- Biology, ChemistryBiochemistry
- 2005
Evidence that Vav2-mediated nucleotide exchange of Rho GTPases follows the Theorell-Chance mechanism is provided and the results suggest that the CRD domain in Vav proteins plays an active role, affecting both the k(on) and the k (cat) for Vav-mediateducleotide exchange on RhoGTPases.
Mechanistic Insights into Specificity, Activity, and Regulatory Elements of the Regulator of G-protein Signaling (RGS)-containing Rho-specific Guanine Nucleotide Exchange Factors (GEFs) p115, PDZ-RhoGEF (PRG), and Leukemia-associated RhoGEF (LARG)*
- Biology, ChemistryThe Journal of Biological Chemistry
- 2011
This comparative study presents detailed kinetic data on specificity, activity, and regulation of the catalytic DH domains of four GEFs, namely p115, p190, PDZ-RhoGEF (PRG), and leukemia-associated Rho GEF (LARG), supporting the proposed models of an intramolecular autoinhibitory mechanism for p115-like RhoGEFs.
RhoGEF Specificity Mutants Implicate RhoA as a Target for Dbs Transforming Activity
- BiologyMolecular and Cellular Biology
- 2002
This study highlights the usefulness of specificity mutants of RhoGEFs as tools to genetically dissect the multiple signaling pathways potentially activated by overexpressed or oncogenic Rho GEFs, as exemplified for Dbs, which is strongly implicated in the transformation of NIH 3T3 cells via RhoA and not Cdc42.
References
SHOWING 1-10 OF 49 REFERENCES
Molecular basis for Rac1 recognition by guanine nucleotide exchange factors
- BiologyNature Structural Biology
- 2001
This work 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 and identified unique GEF specificity determinants in Rac1.
Biochemical analysis of regulation of Vav, a guanine-nucleotide exchange factor for Rho family of GTPases.
- Biology, ChemistryMethods in enzymology
- 2000
Trp56 of Rac1 Specifies Interaction with a Subset of Guanine Nucleotide Exchange Factors*
- Biology, ChemistryThe Journal of Biological Chemistry
- 2001
The results reveal that Rac1 residues of both the switch I and switch II regions are involved in GEF docking and GEF-mediated nucleotide disruption, and suggest that a compound mimicking Trp56 action could be explored as an interfering reagent specifically targeting Rac1 activation.
Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1
- Chemistry, BiologyNature
- 2000
The Tiam1/Rac1 structure highlights the interactions that catalyse nucleotide exchange on RhoFamily G proteins, and illustrates structural determinants dictating specificity between individual Rho family members and their associated Dbl-related guanine nucleotide Exchange factors.
Quantitative Analysis of the Effect of Phosphoinositide Interactions on the Function of Dbl Family Proteins*
- BiologyThe Journal of Biological Chemistry
- 2001
It is demonstrated that the conserved PH domains of three distinct Dbl family proteins, intersectin, Dbs, and Tiam1, selectively bind lipid vesicles only when phosphoinositides are present, suggesting that unless all relevant components are localized to a lipid membrane surface, D Bl family GEFs generally are not intrinsically modulated by binding phosphoinposides.
A crystallographic view of interactions between Dbs and Cdc42: PH domain‐assisted guanine nucleotide exchange
- ChemistryThe EMBO journal
- 2002
Comparative sequence analysis suggests that a subset of Dbl‐family proteins will utilize their PH domains similarly to Dbs, and the Dbs PH domain participates with the DH domain in binding Cdc42, primarily through a set of interactions involving switch 2 of the GTPase.
Identification and Characterization of hPEM-2, a Guanine Nucleotide Exchange Factor Specific for Cdc42*
- BiologyThe Journal of Biological Chemistry
- 1999
Guanine nucleotide exchange factors of the Dbl family regulate the actin cytoskeleton through activation of Rho-like GTPases. At present the Dbl family consists of more than thirty members; many have…
The Pleckstrin Homology Domain Mediates Transformation by Oncogenic Dbl through Specific Intracellular Targeting*
- BiologyThe Journal of Biological Chemistry
- 1996
The results suggest that the dPH domain mediates cellular transformation by targeting the Dbl protein to specific cytoskeletal locations to activate Rho-type small GTP-binding proteins.