A structural model of a Ras–Raf signalosome
| Autor: | Lianbo Li, Jeffrey J. Okoro, Chunya Lu, Kenneth D. Westover, Yibing Shan, Jonas N. Kapp, Chiara Ambrogio, Qi Wang, Pasi A. Jänne, Gabriela Nagy-Davidescu, Xiao Chen Bai, David E. Shaw, Zhi Wei Zhou, Venkatesh Mysore, Andreas Plückthun, Maxwell R. Tucker |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
Galectins MAP Kinase Kinase 1 Guanosine Mutagenesis (molecular biology technique) Molecular Dynamics Simulation Article Proto-Oncogene Proteins p21(ras) Cell membrane chemistry.chemical_compound Microscopy Electron Transmission Structural Biology Fluorescence Resonance Energy Transfer medicine Humans Protein kinase A Molecular Biology Effector Kinase GTPase-Activating Proteins Reproducibility of Results Blood Proteins Cell biology DNA-Binding Proteins Proto-Oncogene Proteins c-raf Microscopy Electron HEK293 Cells medicine.anatomical_structure chemistry Mutagenesis Multiprotein Complexes Guanosine Triphosphate Protein Multimerization Signal transduction Signal Transduction Transcription Factors |
| Zdroj: | Nat Struct Mol Biol Nature Structural and Molecular Biology |
| Popis: | The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the human mitogen-activated protein kinase (MAPK) pathway, which is implicated in many cancers, multiple K-Ras proteins are thought to assemble at the cell membrane with Ras effector proteins from the Raf family. Here we propose an atomistic structural model for such an assembly. Our starting point was an asymmetric guanosine triphosphate-mediated K-Ras dimer model, which we generated using unbiased molecular dynamics simulations and verified with mutagenesis experiments. Adding further K-Ras monomers in a head-to-tail fashion led to a compact helical assembly, a model we validated using electron microscopy and cell-based experiments. This assembly stabilizes K-Ras in its active state and presents composite interfaces to facilitate Raf binding. Guided by existing experimental data, we then positioned C-Raf, the downstream kinase MEK1 and accessory proteins (Galectin-3 and 14-3-3σ) on and around the helical assembly. The resulting Ras-Raf signalosome model offers an explanation for a large body of data on MAPK signaling. |
| Databáze: | OpenAIRE |
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