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Structural basis for the selective activation of Rho GTPases by Dbl exchange factors.
- Source :
-
Nature structural biology [Nat Struct Biol] 2002 Jun; Vol. 9 (6), pp. 468-75. - Publication Year :
- 2002
-
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.
- Subjects :
- Amino Acid Sequence
Crystallography, X-Ray
Enzyme Activation
Guanosine Triphosphate metabolism
Humans
Models, Molecular
Molecular Sequence Data
Protein Structure, Secondary
Protein Structure, Tertiary
Proteins chemistry
Proteins metabolism
Sequence Alignment
Structure-Activity Relationship
Substrate Specificity
T-Lymphoma Invasion and Metastasis-inducing Protein 1
cdc42 GTP-Binding Protein chemistry
cdc42 GTP-Binding Protein metabolism
rac1 GTP-Binding Protein chemistry
rac1 GTP-Binding Protein metabolism
rhoA GTP-Binding Protein chemistry
rhoA GTP-Binding Protein metabolism
Guanine Nucleotide Exchange Factors chemistry
Guanine Nucleotide Exchange Factors metabolism
Proto-Oncogene Proteins chemistry
rho GTP-Binding Proteins chemistry
rho GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1072-8368
- Volume :
- 9
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature structural biology
- Publication Type :
- Academic Journal
- Accession number :
- 12006984
- Full Text :
- https://doi.org/10.1038/nsb796