ArticleThe Biochemical journal2015
Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding.
Article in The Biochemical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
15 citing papers in PubMed, 33 citations in OpenAlex.
- Tunable Aromatic Sulfoxides and Sulfones as Cysteine-Targeting Warheads: Exploring the Structure-Reactivity Relationship.Journal of medicinal chemistry · 2026Article
- Pervanadate-induced oxidation relieves autoinhibition of the protein tyrosine kinase SRC.Science signaling · 2026Article
- Enhancing Selectivity and Potency of SJournal of medicinal chemistry · 2025Article
- Development of CRISPR/Cas9-mediated CD16bFrontiers in immunology · 2025Article
- Protein-Sequence-Based Search of Nonreceptor ITAM-Like Regions to Identify Cytosolic Syk-Recruiting Proteins.The journal of physical chemistry. B · 2024Article
- Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.PloS one · 2024Article
- Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.bioRxiv : the preprint server for biology · 2023Article
- Differences in the dynamics of the tandem-SH2 modules of the Syk and ZAP-70 tyrosine kinases.Protein science : a publication of the Protein Society · 2021Article
- Redox regulation of tyrosine kinase signalling: more than meets the eye.Journal of biochemistry · 2020Review
- Inhibition of T Cell Receptor Activation by Semi-Synthetic Sesquiterpene Lactone Derivatives and Molecular Modeling of Their Interaction with Glutathione and Tyrosine Kinase ZAP-70.Molecules (Basel, Switzerland) · 2019Article
- ZAP-70 in Signaling, Biology, and Disease.Annual review of immunology · 2018Review
- The natural sesquiterpene lactones arglabin, grosheimin, agracin, parthenolide, and estafiatin inhibit T cell receptor (TCR) activation.Phytochemistry · 2018Article
- A highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity.Oncotarget · 2017Article
- Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen.SLAS discovery : advancing life sciences R & D · 2017Article
- A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Zeta-chain associated protein of 70 kDa (ZAP-70) and spleen tyrosine kinase (Syk) are non-receptor tyrosine kinases that are essential for T-cell and B-cell antigen receptor signalling respectively. They are recruited, via their tandem-SH2 (Src-homology domain 2) domains, to doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) on invariant chains of immune antigen receptors. Because of their critical roles in immune signalling, ZAP-70 and Syk are targets for the development of drugs for autoimmune diseases. We show that three thiol-reactive small molecules can prevent the tandem-SH2 domains of ZAP-70 and Syk from binding to phosphorylated ITAMs. We identify a specific cysteine residue in the phosphotyrosine-binding pocket of each protein (Cys39 in ZAP-70, Cys206 in Syk) that is necessary for inhibition by two of these compounds. We also find that ITAM binding to ZAP-70 and Syk is sensitive to the presence of H2O2 and these two cysteine residues are also necessary for inhibition by H2O2. Our findings suggest a mechanism by which the reactive oxygen species generated during responses to antigen could attenuate signalling through these kinases and may also inform the development of ZAP-70 and Syk inhibitors that bind covalently to their SH2 domains.
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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.