ArticleThe Journal of biological chemistry2011
Molecular mechanism of selective recruitment of Syk kinases by the membrane antigen-receptor complex.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 16 citations in OpenAlex.
- Regulating the discriminatory response to antigen by T-cell receptor.Bioscience reports · 2022Review
- Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action inInternational journal of molecular sciences · 2020Article
- The structural basis for membrane assembly of immunoreceptor signalling complexes.Journal of molecular modeling · 2019Article
- A reevaluation of the spleen tyrosine kinase (SYK) activation mechanism.The Journal of biological chemistry · 2019Article
- Non-degradative Ubiquitination of Protein Kinases.PLoS computational biology · 2016Article
- The Structural Basis for Activation and Inhibition of ZAP-70 Kinase Domain.PLoS computational biology · 2015Article
- Two-state dynamics of the SH3-SH2 tandem of Abl kinase and the allosteric role of the N-cap.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ZAP-70 and Syk are essential tyrosine kinases in intracellular immunological signaling. Both contain an inhibitory SH2 domain tandem, which assembles onto the catalytic domain. Upon binding to doubly phosphorylated ITAM motifs on activated antigen receptors, the arrangement of the SH2 domains changes. From available structures, this event is not obviously conducive to dissociation of the autoinhibited complex, yet it ultimately translates into kinase activation through a mechanism not yet understood. We present a comprehensive theoretical study of this molecular mechanism, using atomic resolution simulations and free-energy calculations, totaling >10 μs of simulation time. Through these, we dissect the microscopic mechanism coupling stepwise ITAM engagement and SH2 tandem structural change and reveal key differences between ZAP-70 and Syk. Importantly, we show that a subtle conformational bias in the inter-SH2 connector causes ITAM to bind preferentially to kinase-dissociated tandems. We thus propose that phosphorylated antigen receptors selectively recruit kinases that are uninhibited and that the resulting population shift in the membrane vicinity sustains signal transduction.
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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.