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Raf promotes dimerization of the Ras G-domain with increased allosteric connections.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Mar 09; Vol. 118 (10). - Publication Year :
- 2021
-
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.<br />Competing Interests: The authors declare no competing interest.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 33653954
- Full Text :
- https://doi.org/10.1073/pnas.2015648118