Fluoride complexes of oncogenic Ras mutants to study the Ras-RasGap interaction

Biological Chemistry
Lothar GremerAlfred Wittinghofer

Abstract

Down-regulation of Ras signalling is mediated by specific GTPase-activating proteins (GAPs), which stimulate the very slow GTPase reaction of Ras by 10(5)-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 have 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 find 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 diff...Continue Reading

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Citations

May 9, 2009·Nature Reviews. Molecular Cell Biology·Raphael GasperAlfred Wittinghofer
May 17, 2012·Cancer Research·Ian A PriorCarla Mattos
Jul 24, 2010·Chemico-biological Interactions·Olivier BarbierLuz María Del Razo
Feb 17, 2015·Structure·Susan K FeticsCarla Mattos
Jun 15, 2010·The EMBO Journal·Simone LeonardyLotte Søgaard-Andersen
May 14, 2016·Biological Chemistry·Philipp KnyphausenMichael Lammers
Jun 8, 2017·Genes·Manpreet KalkatLinda Z Penn
Aug 15, 2018·Cold Spring Harbor Perspectives in Medicine·Klaus Scheffzek, Giridhar Shivalingaiah
Mar 15, 2016·Biopolymers·Ashwini K Mishra, David G Lambright
Jan 17, 2020·Cells·Ufuk DegirmenciJiancheng Hu
Sep 26, 2019·Science Signaling·Thomas McFallEdward C Stites
Oct 11, 2019·Biological Chemistry·Raphael Gasper, Fred Wittinghofer
Oct 16, 2019·Proceedings of the National Academy of Sciences of the United States of America·Dana RabaraMatthew Holderfield
Mar 12, 2020·Molecular & Cellular Oncology·Thomas McFall, Edward Cooper Stites
Dec 5, 2017·Acta Crystallographica. Section D, Structural Biology·Shenyuan XuMichael A Kennedy
Jan 9, 2015·Molecular Cancer Research : MCR·Jillian A Parker, Carla Mattos
Apr 17, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kendra Marcus, Carla Mattos
Sep 18, 2020·The Innovation·Delong Jiao, Shengyu Yang

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