1. Allosteric effects of the oncogenic RasQ61L mutant on Raf-RBD.
- Author
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Fetics SK, Guterres H, Kearney BM, Buhrman G, Ma B, Nussinov R, and Mattos C
- Subjects
- Allosteric Regulation, Catalytic Domain, Crystallography, X-Ray, Humans, Hydrogen Bonding, Molecular Dynamics Simulation, Mutation, Missense, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, Quaternary, Protein Structure, Secondary, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins c-raf chemistry, Proto-Oncogene Proteins p21(ras) chemistry
- Abstract
The Ras/Raf/MEK/ERK signal transduction pathway is a major regulator of cell proliferation activated by Ras-guanosine triphosphate (GTP). The oncogenic mutant RasQ61L is not able to hydrolyze GTP in the presence of Raf and thus is a constitutive activator of this mitogenic pathway. The Ras/Raf interaction is essential for the activation of the Raf kinase domain through a currently unknown mechanism. We present the crystal structures of the Ras-GppNHp/Raf-RBD and RasQ61L-GppNHp/Raf-RBD complexes, which, in combination with MD simulations, reveal differences in allosteric interactions leading from the Ras/Raf interface to the Ras calcium-binding site and to the remote Raf-RBD loop L4. In the presence of Raf, the RasQ61L mutant has a rigid switch II relative to the wild-type and increased flexibility at the interface with switch I, which propagates across Raf-RBD. We show that in addition to local perturbations on Ras, RasQ61L has substantial long-range effects on the Ras allosteric lobe and on Raf-RBD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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