Raf promotes dimerization of the Ras G-domain with increased allosteric connections

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. Com...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (10), p.1-11
Main Authors: Packer, Morgan R., Parker, Jillian A., Chung, Jean K., Li, Zhenlu, Lee, Young Kwang, Cookis, Trinity, Guterres, Hugo, Alvarez, Steven, Hossain, Md Amin, Donnelly, Daniel P., Agar, Jeffrey N., Makowski, Lee, Buck, Matthias, Groves, Jay T., Mattos, Carla
Format: Article
Language:English
Subjects:
Allosteric properties
Binding sites
Biological Sciences
Dimerization
Dimers
Domains
Galectins - chemistry
Galectins - genetics
Galectins - metabolism
Humans
Lipid bilayers
Lipids
Macromolecules
Metabolic pathways
Molecular dynamics
Molecular Dynamics Simulation
Network analysis
Protein Domains
Proto-Oncogene Proteins p21(ras) - chemistry
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
raf Kinases - chemistry
raf Kinases - genetics
raf Kinases - metabolism
Raf protein
Ras protein
Robustness
Signaling
Size exclusion chromatography
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Summary: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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2015648118