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A structural model of a Ras-Raf signalosome.
Mysore, Venkatesh P; Zhou, Zhi-Wei; Ambrogio, Chiara; Li, Lianbo; Kapp, Jonas N; Lu, Chunya; Wang, Qi; Tucker, Maxwell R; Okoro, Jeffrey J; Nagy-Davidescu, Gabriela; Bai, Xiaochen; Plückthun, Andreas; Jänne, Pasi A; Westover, Kenneth D; Shan, Yibing; Shaw, David E.
Afiliación
  • Mysore VP; D. E. Shaw Research, New York, NY, USA.
  • Zhou ZW; Departments of Biochemistry and Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Ambrogio C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Li L; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
  • Kapp JN; Departments of Biochemistry and Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Lu C; Department of Biochemistry, University of Zürich, Zürich, Switzerland.
  • Wang Q; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Tucker MR; Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • Okoro JJ; D. E. Shaw Research, New York, NY, USA.
  • Nagy-Davidescu G; D. E. Shaw Research, New York, NY, USA.
  • Bai X; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Plückthun A; Department of Biochemistry, University of Zürich, Zürich, Switzerland.
  • Jänne PA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Westover KD; Department of Biochemistry, University of Zürich, Zürich, Switzerland.
  • Shan Y; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Shaw DE; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Struct Mol Biol ; 28(10): 847-857, 2021 10.
Article en En | MEDLINE | ID: mdl-34625747
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas p21(ras) / Proteínas Proto-Oncogénicas c-raf Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas p21(ras) / Proteínas Proto-Oncogénicas c-raf Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos