1. Raf promotes dimerization of the Ras G-domain with increased allosteric connections.
- Author
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Packer MR, Parker JA, Chung JK, Li Z, Lee YK, Cookis T, Guterres H, Alvarez S, Hossain MA, Donnelly DP, Agar JN, Makowski L, Buck M, Groves JT, and Mattos C
- Subjects
- Galectins chemistry, Galectins genetics, Galectins metabolism, Humans, Protein Domains, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, raf Kinases genetics, raf Kinases metabolism, Molecular Dynamics Simulation, Proto-Oncogene Proteins p21(ras) chemistry, raf Kinases chemistry
- Abstract
Ras dimerization is critical for Raf activation. Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics simulations shows robust allosteric connections linking the two Raf-RBD D113 residues located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 Å apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway., Competing Interests: The authors declare no competing interest.
- Published
- 2021
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