Structure and mutagenesis of the Dbl homology domain
Abstract
Guanine nucleotide exchange factors in the Dbl family activate Rho GTPases by accelerating dissociation of bound GDP, promoting acquisition of the GTP-bound state. Dbl proteins possess a approximately 200 residue catalytic Dbl-homology (DH) domain, that is arranged in tandem with a C-terminal pleckstrin homology (PH) domain in nearly all cases. Here we report the solution structure of the DH domain of human PAK-interacting exchange protein (betaPIX). The domain is composed of 11 alpha-helices that form a flattened, elongated bundle. The structure explains a large body of mutagenesis data, which, along with sequence comparisons, identify the GTPase interaction site as a surface formed by three conserved helices near the center of one face of the domain. Proximity of the site to the DH C-terminus suggests a means by which PH-ligand interactions may be coupled to DH-GTPase interactions to regulate signaling through the Dbl proteins in vivo.
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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 [26]
Cites
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“The structure shows only minimal similarity to proteins in the structural database (maximum DAL”
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Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex
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Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors
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- Authors
- Aghazadeh, B., Zhu, K., Kubiseski, T. J., Liu, G. A., Pawson, T., Zheng, Y., & Rosen, M. K.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Mount Sinai Hospital (CA)
- Corresponding author
- Rosen, Michael K.
- Venue
- Nature Structural Biology
- Published
- 1998-12
- Volume
- 5
- Issue
- 12
- Pages
- 1098-1107
- ISSN
- 1072-8368 (ISSN-L)
- DOI
- 10.1038/4209
- OpenAlex
- W2030616863
- Cited by
- 145
- References
- 2
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 1 · 2014: 5 · 2013: 3 · 2012: 2
- FWCI
- 4.60
- 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 › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Dbl homology domain, guanine nucleotide exchange factor, Rho GTPase activation, betaPIX, pleckstrin homology domain, solution structure, alpha-helix bundle, mutagenesis, protein-protein interaction, signaling regulation
- MeSH terms
- Amino Acid Sequence, Blood Proteins, Enzyme Activation, Escherichia coli, Guanosine Diphosphate, Humans, Models, Molecular, Molecular Sequence Data, Nerve Tissue Proteins, Magnetic Resonance Spectroscopy, Phosphoproteins, Proteins, Proto-Oncogene Proteins, Helminth Proteins, Mutagenesis, Site-Directed, Frameshift Mutation, Sequence Alignment, Sequence Homology, Amino Acid, Cell Cycle Proteins, GTP-Binding Proteins, Catalytic Domain, GTP Phosphohydrolases, Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, cdc42 GTP-Binding Protein, Caenorhabditis elegans Proteins, Rho Guanine Nucleotide Exchange Factors
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