ArticleBiophysical journal2009
Molecular dynamics simulations reveal that Tyr-317 phosphorylation reduces Shc binding affinity for phosphotyrosyl residues of epidermal growth factor receptor.
Article in Biophysical journal, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- Evolutionary Couplings and Molecular Dynamic Simulations Highlight Details of GPCRs Heterodimers' Interfaces.Molecules (Basel, Switzerland) · 2023Article
- A survey of multiscale modeling: Foundations, historical milestones, current status, and future prospects.AIChE journal. American Institute of Chemical Engineers · 2021Article
- Fortilin binds IRE1α and prevents ER stress from signaling apoptotic cell death.Nature communications · 2017Article
- Understanding the molecular basis of substrate binding specificity of PTB domains.Scientific reports · 2016Article
- All-atom molecular dynamics analysis of multi-peptide systems reproduces peptide solubility in line with experimental observations.Scientific reports · 2016Article
- The ShcD signaling adaptor facilitates ligand-independent phosphorylation of the EGF receptor.Molecular biology of the cell · 2014Article
- Engineering a single ubiquitin ligase for the selective degradation of all activated ErbB receptor tyrosine kinases.Oncogene · 2014Article
- Physicochemical mechanisms of protein regulation by phosphorylation.Frontiers in genetics · 2014Review
- Structural systems biology and multiscale signaling models.Annals of biomedical engineering · 2012Review
- An adaptive coarse graining method for signal transduction in three dimensions.Fundamenta informaticae · 2012Article
- Dynamic conformational changes in munc18 prevent syntaxin binding.PLoS computational biology · 2011Article
- Investigating Molecular Mechanisms of Activation and Mutation of the HER2 Receptor Tyrosine Kinase through Computational Modeling and Simulation.Cancer research journal · 2011Article
- Molecular systems biology of ErbB1 signaling: bridging the gap through multiscale modeling and high-performance computing.Molecular bioSystems · 2008Article
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
The Src homology 2 (SH2) and collagen domain protein Shc plays a pivotal role in signaling via tyrosine kinase receptors, including epidermal growth factor receptor (EGFR). Shc binding to phospho-tyrosine residues on activated receptors is mediated by the SH2 and phospho-tyrosine binding (PTB) domains. Subsequent phosphorylation on Tyr-317 within the Shc linker region induces Shc interactions with Grb2-Son of Sevenless that initiate Ras-mitogen-activated protein kinase signaling. We use molecular dynamics simulations of full-length Shc to examine how Tyr-317 phosphorylation controls Shc conformation and interactions with EGFR. Our simulations reveal that Shc tyrosine phosphorylation results in a significant rearrangement of the relative position of its domains, suggesting a key conformational change. Importantly, computational estimations of binding affinities show that EGFR-derived phosphotyrosyl peptides bind with significantly more strength to unphosphorylated than to phosphorylated Shc. Our results unveil what we believe is a novel structural phenomenon, i.e., tyrosine phosphorylation of Shc within its linker region regulates the binding affinity of SH2 and PTB domains for phosphorylated Shc partners, with important implications for signaling dynamics.
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