title: Allosteric effects of the oncogenic RasQ61L mutant on Raf-RBD.
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.
authors: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.
authors: Susan K
authors: SK
authors: Fetics
authors: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
authors: Hugo
authors: H
authors: Guterres
authors: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.
authors: Bradley M
authors: BM
authors: Kearney
authors: Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.
authors: Greg
authors: G
authors: Buhrman
authors: Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
authors: Buyong
authors: B
authors: Ma
authors: Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA; Department of Human Genetics, Sackler Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors: Ruth
authors: R
authors: Nussinov
authors: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA. Electronic address: c.mattos@neu.edu.
authors: Carla
authors: C
authors: Mattos
mesh_terms: D000494:Allosteric Regulation; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry*; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000235:genetics
chemical_list: D019908:Proto-Oncogene Proteins c-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)