The isolated catalytic hairpin of the Ras-specific guanine nucleotide exchange factor Cdc25Mm retains nucleotide dissociation activity but has impaired nucleotide exchange activity
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Sacco, E
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Fantinato, S
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Univ Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, ItalyUniv Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, Italy
Fantinato, S
[1
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Manzoni, R
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Univ Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, ItalyUniv Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, Italy
Manzoni, R
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Metalli, D
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Univ Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, ItalyUniv Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, Italy
Metalli, D
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De Gioia, L
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Univ Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, ItalyUniv Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, Italy
De Gioia, L
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Fantucci, P
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Univ Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, ItalyUniv Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, Italy
Fantucci, P
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Alberghina, L
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Univ Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, ItalyUniv Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, Italy
Alberghina, L
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Vanoni, M
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Univ Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, ItalyUniv Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, Italy
Vanoni, M
[1
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[1] Univ Milan, Dipartimento Biotechnol & Biosci, I-20126 Milan, Italy
Cdc25(Mm) 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 Cdc25(MnT1184E), 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. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.