ArticleNature structural & molecular biology2021
A structural model of a Ras-Raf signalosome.
Article in Nature structural & molecular biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 67 citations in OpenAlex.
- Article
- NRas Nanoclusters Mediate Crosstalk Between BRAF/ERK and PI3K/AKT Signaling in Melanoma Cells.International journal of molecular sciences · 2025Article
- A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.Molecular oncology · 2025Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Insight into molecular basis and dynamics of full-length CRaf kinase in cellular signaling mechanisms.Biophysical journal · 2024Article
- Intracellular galectin interactions in health and disease.Seminars in immunopathology · 2024Review
- RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.The Journal of cell biology · 2024Article
- Crystal Packing Reveals a Potential Autoinhibited KRAS Dimer Interface and a Strategy for Small-Molecule Inhibition of RAS Signaling.Biochemistry · 2023Article
- GLUT3 promotes macrophage signaling and function via RAS-mediated endocytosis in atopic dermatitis and wound healing.The Journal of clinical investigation · 2023Article
- Mechanism-Based Redesign of GAP to Activate Oncogenic Ras.Journal of the American Chemical Society · 2023Article
- Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation.JCI insight · 2023Article
- The E3/E4 ubiquitin ligase UFD-2 suppresses normal and oncogenic signaling mediated by a Raf ortholog inScience signaling · 2023Article
- Genetic variants of SOS2, MAP2K1 and RASGRF2 in the RAS pathway genes predict survival of HBV-related hepatocellular carcinoma patients.Archives of toxicology · 2023Article
- Chimera and Tandem-Repeat Type Galectins: The New Targets for Cancer Immunotherapy.Biomolecules · 2023Review
- Consensus on the RAS dimerization hypothesis: Strong evidence for lipid-mediated clustering but not for G-domain-mediated interactions.Molecular cell · 2023Review
- Lifetime of actin-dependent protein nanoclusters.Biophysical journal · 2023Article
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death.International journal of molecular sciences · 2023Article
- NRas activity is regulated by dynamic interactions with nanoscale signaling clusters at the plasma membrane.iScience · 2022Article
- Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces.Biophysical journal · 2022Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.