ArticleStructure (London, England : 1993)2024
The mechanism of allosteric activation of SYK kinase derived from multiple phospho-ITAM-bound structures.
Article in Structure (London, England : 1993), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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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
6 citing papers in PubMed.
- Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.Molecular therapy. Oncology · 2026Review
- Amphioxus tyrosine kinase SYK inhibits NF-κB activation through MyD88-dependent mechanism.Journal of molecular cell biology · 2026Article
- Non-receptor tyrosine kinase signaling pathways and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- Microglial ITAM & ITIM Signaling in Neurodegenerative Disease and Brain Aging.Journal of molecular biology · 2026Review
- Gut microbiota dysbiosis and host metabolite-immune crosstalk drives the pathogenesis of neonatal lupus erythematosus: a multi-omics analysis.BMC medicine · 2026Article
- Syk activation during FcγR-mediated phagocytosis involves Syk palmitoylation and desulfenylation.Life science alliance · 2026Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Spleen tyrosine kinase (SYK) is central to adaptive and innate immune signaling. It features a regulatory region containing tandem SH2 (tSH2) domains separated by a helical "hinge" segment keeping SYK inactive by associating with the kinase domain. SYK activation is triggered when the tSH2 domains bind to a phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) found on receptor tails. Past mutational studies have indicated that ITAM binding disrupts the hinge-kinase interaction, leading to SYK phosphorylation and activation. However, the mechanism of this process is unclear, as the ITAM interaction occurs far from the hinge region. We have determined crystal structures of three phospho-ITAMs in complex with the tSH2 domains, revealing a highly conserved binding mechanism. These structures, together with mutational studies and biophysical analyses, reveal that phospho-ITAM binding restricts SH2 domain movement and causes allosteric changes in the hinge region. These changes are not compatible with the association of the kinase domain, leading to kinase activation.
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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 Socratic graph.