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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Blood Proteins / chemistry*
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Blood Proteins / genetics
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Caenorhabditis elegans Proteins*
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Catalytic Domain / genetics*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Enzyme Activation
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Escherichia coli
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Frameshift Mutation
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism*
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism
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Guanine Nucleotide Exchange Factors
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Guanosine Diphosphate / metabolism
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Helminth Proteins / genetics
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Helminth Proteins / metabolism
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Humans
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Phosphoproteins*
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / genetics
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Rho Guanine Nucleotide Exchange Factors
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Sequence Alignment
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Sequence Homology, Amino Acid*
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cdc42 GTP-Binding Protein
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rhoA GTP-Binding Protein
Substances
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Blood Proteins
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Caenorhabditis elegans Proteins
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Cell Cycle Proteins
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FGD1 protein, human
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Guanine Nucleotide Exchange Factors
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Helminth Proteins
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MCF2 protein, human
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Nerve Tissue Proteins
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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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Rho Guanine Nucleotide Exchange Factors
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UNC-73 protein, C elegans
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platelet protein P47
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Guanosine Diphosphate
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GTP Phosphohydrolases
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GTP-Binding Proteins
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cdc42 GTP-Binding Protein
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rhoA GTP-Binding Protein