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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred


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1437-4315
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Fluoride complexes of oncogenic Ras mutants to study the Ras-RasGAP interaction

Lothar Gremer1 / Bernd Gilsbach2 / Mohammad Reza Ahmadian3 / Alfred Wittinghofer4

1Abteilung Strukturelle Biologie, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Straße 11, D-44227 Dortmund, Germany

2Abteilung Strukturelle Biologie, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Straße 11, D-44227 Dortmund, Germany

3Institut für Biochemie und Molekularbiologie II, Klinikum der Heinrich-Heine-Universität, Universitätsstraße 1, Gebäude 22.03, D-40225 Düsseldorf, Germany

4Abteilung Strukturelle Biologie, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Straße 11, D-44227 Dortmund, Germany

Corresponding author

Citation Information: Biological Chemistry. Volume 389, Issue 9, Pages 1163–1171, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2008.132, August 2008

Publication History

Received:
2007-12-23
Accepted:
2008-04-01
Published Online:
2008-08-19

Abstract

Down-regulation of Ras signalling is mediated by specific GTPase-activating proteins (GAPs), which stimulate the very slow GTPase reaction of Ras by 105-fold. The basic features of the GAP activity involve the stabilisation of both switch regions of Ras in the transition state, and the insertion of an arginine finger. In the case of oncogenic Ras mutations, the features of the active site are disturbed. To understand these features in more detail, we investigated the effects of oncogenic mutations of Ras and compared the GAP-stimulated GTPase reaction with the ability to form GAP-mediated aluminium or beryllium fluoride complexes. In general, we found a correlation between the size of the amino acid at position 12, the GTPase activity and ability to form aluminium fluoride complexes. While Gly12 is very sensitive to even the smallest possible structural change, Gly13 is much less sensitive to steric hindrance, but is sensitive to charge. Oncogenic mutants of Ras defective in the GTPase activity can however form ground-state GppNHp complexes with GAP, which can be mimicked by beryllium fluoride binding. We show that beryllium fluoride complexes are less sensitive to structural changes and report on a state close to but different from the ground state of the GAP-stimulated GTPase reaction.

Keywords: aluminium fluoride; beryllium fluoride; GTPase; GTPase-activating protein; neurofibromin; oncogene; Ras; transition state

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