ArticleJournal of the American Chemical Society2020
High-Affinity Interactions of the nSH3/cSH3 Domains of Grb2 with the C-Terminal Proline-Rich Domain of SOS1.
Article in Journal of the American Chemical Society, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 37 citations in OpenAlex.
- Article
- DDX42 Enhances Hepatocellular Carcinoma Cell Proliferation, Radiation and Sorafenib Resistance via Regulating GRB2 RNA Maturation and Activating PI3K/AKT Pathway.Journal of cellular and molecular medicine · 2025Article
- Osteoblast-Derived ECM1 Promotes Anti-Androgen Resistance in Bone Metastatic Prostate Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Targeting Grb2 SH3 Domains with Affimer Proteins Provides Novel Insights into Ras Signalling Modulation.Biomolecules · 2024Article
- Porcine deltacoronavirus nucleocapsid protein interacts with the Grb2 through its proline-rich motifs to induce activation of the Raf-MEK-ERK signal pathway and promote virus replication.The Journal of general virology · 2024Article
- The Configuration of GRB2 in Protein Interaction and Signal Transduction.Biomolecules · 2024Review
- Interactions of the N- and C-Terminal SH3 Domains ofInternational journal of molecular sciences · 2023Article
- Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes.Science advances · 2022Article
- Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.Journal of molecular biology · 2022Review
- The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia.Biophysical journal · 2022Article
- Mechanism of activation and the rewired network: New drug design concepts.Medicinal research reviews · 2022Review
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
- Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect.Frontiers in molecular biosciences · 2022Article
- Allosteric regulation of GRB2 modulates RAS activation.Small GTPases · 2022Article
- Inhibition of Nonfunctional Ras.Cell chemical biology · 2021Review
- Hey1 promotes migration and invasion of melanoma cells via GRB2/PI3K/AKT signaling cascade.Journal of Cancer · 2021Article
- Neuroprotective Effects of ZiBuPiYin Recipe on db/db Mice via PI3K-Akt Signaling Pathway by Activating Grb2.Neural plasticity · 2021Article
- Proline-rich domain of human ALIX contains multiple TSG101-UEV interaction sites and forms phosphorylation-mediated reversible amyloids.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- SOS1 interacts with Grb2 through regions that induce closed nSH3 conformations.The Journal of chemical physics · 2020Article
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Grb2 is an adaptor protein that recruits Ras-specific guanine nucleotide exchange factor, Son of Sevenless 1 (SOS1), to the plasma membrane. SOS1 exchanges GDP by GTP, activating Ras. Grb2 consists of an SH2 domain flanked by N- and C-terminal SH3 domains (nSH3/cSH3). Grb2 nSH3/cSH3 domains have strong binding affinity for the SOS1 proline-rich (PR) domain that mediates the Grb2-SOS1 interaction. The nSH3/cSH3 domains have distinct preferred binding motifs: PxxPxR for nSH3 and PxxxRxxKP for cSH3 (x represents any natural amino acid). Several nSH3-binding motifs have been identified in the SOS1 PR domain but none specific for cSH3 binding. Even though both nSH3 and cSH3 exhibit the strongest binding to the SOS1 peptide PVPPPVPPRRRP, this mutually exclusive binding combined with other potential nSH3/cSH3 binding regions in SOS1 makes understanding the Grb2-SOS1 interaction challenging. To identify the SOS1-cSH3 binding sites, we selected seven potential binding segments in SOS1. The synthesized peptides were tested for their binding to nSH3/cSH3. Our NMR data reveal that the PKLPPKTYKREH peptide has strong binding affinity for cSH3, but very weak for nSH3. The binding specificity suggests that the most likely Grb2-SOS1 binding mode is through nSH3-PVPPPVPPRRRP and cSH3-PKLPPKTYKREH interactions, which is supported by replica-exchange simulations for the Grb2-SOS1 complex models. We propose that nSH3/cSH3 binding peptides, which effectively interrupt Grb2-SOS1 association, can serve as tumor suppressors. The Grb2-SOS1 mechanism outlined here offers new venues for future therapeutic strategies for upstream mutations in cancer, such as in EGFR.
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