ArticleJournal of the American Chemical Society2017
Allosteric Modulation of Grb2 Recruitment to the Intrinsically Disordered Scaffold Protein, LAT, by Remote Site Phosphorylation.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 30 citations in OpenAlex.
- Review
- Article
- A unifying model of LAT condensates in reconstitution experiments.bioRxiv : the preprint server for biology · 2025Article
- Update on Structure and Function of SH2 Domains: Mechanisms and Emerging Targeting Strategies.International journal of molecular sciences · 2025Review
- Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.Science advances · 2024Article
- The molecular basis for cellular function of intrinsically disordered protein regions.Nature reviews. Molecular cell biology · 2024Review
- Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2.eLife · 2023Article
- NMR Relaxation Dispersion Experiments to Study Phosphopeptide Recognition by SH2 Domains: The Grb2-SH2-Phosphopeptide Encounter Complex.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Discrete LAT condensates encode antigen information from single pMHC:TCR binding events.Nature communications · 2022Article
- Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes.Science advances · 2022Article
- MVsim is a toolset for quantifying and designing multivalent interactions.Nature communications · 2022Article
- The relative binding position of Nck and Grb2 adaptors impacts actin-based motility of Vaccinia virus.eLife · 2022Article
- A two-component protein condensate of the EGFR cytoplasmic tail and Grb2 regulates Ras activation by SOS at the membrane.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation.Nature immunology · 2022Article
- Systems-level conservation of the proximal TCR signaling network of mice and humans.The Journal of experimental medicine · 2022Article
- Article
- Article
- The dynamics of free and phosphopeptide-bound Grb2-SH2 reveals two dynamically independent subdomains and an encounter complex with fuzzy interactions.Scientific reports · 2020Article
- Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior.Current opinion in structural biology · 2020Review
- Regulation of Transmembrane Signaling by Phase Separation.Annual review of biophysics · 2019Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Tyrosine phosphorylation of membrane receptors and scaffold proteins followed by recruitment of SH2 domain-containing adaptor proteins constitutes a central mechanism of intracellular signal transduction. During early T-cell receptor (TCR) activation, phosphorylation of linker for activation of T cells (LAT) leading to recruitment of adaptor proteins, including Grb2, is one prototypical example. LAT contains multiple modifiable sites, and this multivalency may provide additional layers of regulation, although this is not well understood. Here, we quantitatively analyze the effects of multivalent phosphorylation of LAT by reconstituting the initial reactions of the TCR signaling pathway on supported membranes. Results from a series of LAT constructs with combinatorial mutations of tyrosine residues reveal a previously unidentified allosteric mechanism in which the binding affinity of LAT:Grb2 depends on the phosphorylation at remote tyrosine sites. Additionally, we find that LAT:Grb2 binding affinity is altered by membrane localization. This allostery mainly regulates the kinetic on-rate, not off-rate, of LAT:Grb2 interactions. LAT is an intrinsically disordered protein, and these data suggest that phosphorylation changes the overall ensemble of configurations to modulate the accessibility of other phosphorylated sites to Grb2. Using Grb2 as a phosphorylation reporter, we further monitored LAT phosphorylation by TCR ζ chain-recruited ZAP-70, which suggests a weakly processive catalysis on membranes. Taken together, these results suggest that signal transmission through LAT is strongly gated and requires multiple phosphorylation events before efficient signal transmission is achieved.
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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.