The isolated catalytic hairpin of the Ras‐specific guanine nucleotide exchange factor Cdc25Mm retains nucleotide dissociation activity but has impaired nucleotide exchange activity
Copyright policy )The isolated catalytic hairpin of the Ras‐specific guanine nucleotide exchange factor Cdc25Mm retains nucleotide dissociation activity but has impaired nucleotide exchange activity
Cdc25Mm is a mammalian Ras‐specific guanine nucleotide exchange factor (GEF). By homology modeling we show that it shares with Sos‐GEF the structure of the putative catalytic HI hairpin where the dominant negative T1184E mutation is located. Similarly to Cdc25MmT1184E, the isolated wild‐type and mutant hairpins retain the ability to displace Ras‐bound nucleotide, originate a stable Ras/GEF complex and downregulate the Ras pathway in vivo. These results indicate that nucleotide re‐entry and Ras/GEF dissociation – final steps in the GEF catalytic cycle – require GEF regions different from the HI hairpin. GEF down‐sizing could lead to development of novel Ras inhibitors.
- University of Milan Italy
- University of Milano-Bicocca Italy
Down-Regulation, Glutamic Acid, HI hairpin, Ras inhibitor, Buffers, Crystallography, X-Ray, Guanosine Diphosphate, Catalysis, Genes, Reporter, Catalytic Domain, Escherichia coli, Animals, Amino Acid Sequence, Luciferases, Cdc25Mm, Cell Line, Transformed, Genes, Dominant, Homozygote, Fibroblasts, Catalytic Domain; Genes, Dominant; Temperature; Catalysis; Anthranilic Acids; ras-GRF1; Cell Line, Transformed; Buffers; Genes, ras; Fibroblasts; Homozygote; Glutamic Acid; Cell Transformation, Neoplastic; Sequence Homology, Amino Acid; Mice; Molecular Sequence Data; Amino Acid Sequence; Genes, Reporter; Luciferases; Guanosine Diphosphate; Escherichia coli; Amino Acid Substitution; Protein Structure, Secondary; Down-Regulation; Animals; Models, Molecular; Guanosine Triphosphate; NIH 3T3 Cells; Crystallography, X-Ray, Cell Transformation, Neoplastic, Genes, ras, Amino Acid Substitution, Dominant negative mutants, Guanosine Triphosphate, Guanine nucleotide exchange factor
Down-Regulation, Glutamic Acid, HI hairpin, Ras inhibitor, Buffers, Crystallography, X-Ray, Guanosine Diphosphate, Catalysis, Genes, Reporter, Catalytic Domain, Escherichia coli, Animals, Amino Acid Sequence, Luciferases, Cdc25Mm, Cell Line, Transformed, Genes, Dominant, Homozygote, Fibroblasts, Catalytic Domain; Genes, Dominant; Temperature; Catalysis; Anthranilic Acids; ras-GRF1; Cell Line, Transformed; Buffers; Genes, ras; Fibroblasts; Homozygote; Glutamic Acid; Cell Transformation, Neoplastic; Sequence Homology, Amino Acid; Mice; Molecular Sequence Data; Amino Acid Sequence; Genes, Reporter; Luciferases; Guanosine Diphosphate; Escherichia coli; Amino Acid Substitution; Protein Structure, Secondary; Down-Regulation; Animals; Models, Molecular; Guanosine Triphosphate; NIH 3T3 Cells; Crystallography, X-Ray, Cell Transformation, Neoplastic, Genes, ras, Amino Acid Substitution, Dominant negative mutants, Guanosine Triphosphate, Guanine nucleotide exchange factor
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