A detailed thermodynamic analysis of ras/effector complex interfaces

Journal of Molecular Biology
Christina KielC Herrmann

Abstract

Many cellular functions are based on the interaction and crosstalk of various signaling proteins. Among these, members of the Ras family of small GTP-binding proteins are important for communicating signals into different pathways. In order to answer the question of how binding affinity and specificity is achieved, we analyzed binding energetics on the molecular level, with reference to the available structural data. The interaction of two members of the Ras subfamily with two different effector proteins, namely Raf and RalGDS, were investigated using isothermal titration calorimetry and a fluorescence-based method. Experiments with alanine mutants, located in the complex interfaces, yielded an energy map for the contact areas of the Ras/effector complexes, which could be differentiated into enthalpy and entropy contributions. In addition, by using double mutant cycle analysis, we probed the energetic contribution of selected pairs of amino acid residues. The resulting energy landscapes of the Ras/effector interface areas show a highly different topology when comparing the two effectors, Raf and RalGDS, demonstrating the specificity of the respective interactions. Particularly, we observe a high degree of compensating effects b...Continue Reading

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Citations

Mar 21, 2008·Molecular BioSystems·Lawrence E Goldfinger
Jul 14, 2009·Molecular BioSystems·M Michael GromihaKazuhiko Fukui
Jun 28, 2005·Nucleic Acids Research·Joost SchymkowitzLuis Serrano
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