ArticleProceedings of the National Academy of Sciences of the United States of America2010
Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 97 citations in OpenAlex.
- Disrupting the KRAS-SOS1 protein-protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy.Frontiers in chemistry · 2026Review
- Guanine Nucleotide Exchange Factors and Small GTPases: Their Regulation and Functions, Diseases, and Therapeutic Targets.MedComm · 2025Review
- Genetic and oncogenic features of RASGRF fusions.NPJ precision oncology · 2025Article
- Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens.Nature biotechnology · 2025Article
- Article
- Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism.Biophysical journal · 2024Article
- Histones and histone variant families in prokaryotes.Nature communications · 2024Article
- Pathogen-specific structural features ofmBio · 2023Article
- Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.Science advances · 2023Article
- PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Cutis verticis gyrata and Noonan syndrome: report of two cases with pathogenetic variant in SOS1 gene.Italian journal of pediatrics · 2022Article
- The RASopathies: from pathogenetics to therapeutics.Disease models & mechanisms · 2022Review
- Article
- Relating cellular signaling timescales to single-molecule kinetics: A first-passage time analysis of Ras activation by SOS.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Interactions between Phase-Separated Liquids and Membrane Surfaces.Applied sciences (Basel, Switzerland) · 2021Article
- Regulation of the Small GTPase Ras and Its Relevance to Human Disease.Methods in molecular biology (Clifton, N.J.) · 2021Review
- Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives.Biomolecules · 2020Review
- The hanging heart: How KRAS lures its prey to the membrane.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Article
- Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
Membrane-bound Ras is activated by translocation of the Son of Sevenless (SOS) protein to the plasma membrane. SOS is inactive unless Ras is bound to an allosteric site on SOS, and the Dbl homology (DH) and Pleckstrin homology (PH) domains of SOS (the DH-PH unit) block allosteric Ras binding. We showed previously that the activity of SOS at the membrane increases with the density of PIP(2) and the local concentration of Ras-GTP, which synergize to release the DH-PH unit. Here we present a new crystal structure of SOS that contains the N-terminal histone domain in addition to the DH-PH unit and the catalytic unit (SOS(HDFC), residues 1-1049). The structure reveals that the histone domain plays a dual role in occluding the allosteric site and in stabilizing the autoinhibitory conformation of the DH-PH unit. Additional insight is provided by kinetic analysis of the activation of membrane-bound Ras by mutant forms of SOS that contain mutations in the histone and the PH domains (E108K, C441Y, and E433K) that are associated with Noonan syndrome, a disease caused by hyperactive Ras signaling. Our results indicate that the histone domain and the DH-PH unit are conformationally coupled, and that the simultaneous engagement of the membrane by a PH domain PIP(2)-binding interaction and electrostatic interactions between a conserved positively charged patch on the histone domain and the negatively charged membrane coincides with a productive reorientation of SOS at the membrane and increased accessibility of both Ras binding sites on SOS.
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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.