ArticleProtein science : a publication of the Protein Society2021
Differences in the dynamics of the tandem-SH2 modules of the Syk and ZAP-70 tyrosine kinases.
Article in Protein science : a publication of the Protein Society, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 25 citations in OpenAlex.
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- An electrostatic network with strong connectivity is a phospho-sensor for regulating affinity of Syk-receptor association.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The structural influence of the oncogenic driver mutation N642H in the STAT5B SH2 domain.Protein science : a publication of the Protein Society · 2025Article
- The mechanism of allosteric activation of SYK kinase derived from multiple phospho-ITAM-bound structures.Structure (London, England : 1993) · 2024Article
- Protein-Sequence-Based Search of Nonreceptor ITAM-Like Regions to Identify Cytosolic Syk-Recruiting Proteins.The journal of physical chemistry. B · 2024Article
- CAR Macrophages: a promising novel immunotherapy for solid tumors and beyond.Biomarker research · 2024Review
- Non-Receptor Tyrosine Kinases: Their Structure and Mechanistic Role in Tumor Progression and Resistance.Cancers · 2024Review
- Regulation of BCR-dependent germinal center B-cell formation by HGAL and insight into its emerging myeloid ortholog, C1ORF150.Frontiers in immunology · 2024Review
- Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases.Heliyon · 2023Review
- Tandem engagement of phosphotyrosines by the dual SH2 domains of p120RasGAP.Structure (London, England : 1993) · 2022Article
- Saturation mutagenesis of a predicted ancestral Syk-family kinase.Protein science : a publication of the Protein Society · 2022Article
- Regulating the discriminatory response to antigen by T-cell receptor.Bioscience reports · 2022Review
- 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
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Authors and funding
6 authors at 2 institutions in 1 country.
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Abstract
The catalytic activity of Syk-family tyrosine kinases is regulated by a tandem Src homology 2 module (tSH2 module). In the autoinhibited state, this module adopts a conformation that stabilizes an inactive conformation of the kinase domain. The binding of the tSH2 module to phosphorylated immunoreceptor tyrosine-based activation motifs necessitates a conformational change, thereby relieving kinase inhibition and promoting activation. We determined the crystal structure of the isolated tSH2 module of Syk and find, in contrast to ZAP-70, that its conformation more closely resembles that of the peptide-bound state, rather than the autoinhibited state. Hydrogen-deuterium exchange by mass spectrometry, as well as molecular dynamics simulations, reveal that the dynamics of the tSH2 modules of Syk and ZAP-70 differ, with most of these differences occurring in the C-terminal SH2 domain. Our data suggest that the conformational landscapes of the tSH2 modules in Syk and ZAP-70 have been tuned differently, such that the autoinhibited conformation of the Syk tSH2 module is less stable. This feature of Syk likely contributes to its ability to more readily escape autoinhibition when compared to ZAP-70, consistent with tighter control of downstream signaling pathways in T cells.
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