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- W2901431507 abstract "ABSTRACT Syk/Zap70 family kinases are essential for signaling via multichain immune-recognition receptors such as the tetrameric (αβγ2) FcεRI The simplest model assumes that Syk activation occurs through cis binding of its tandem SH2 domains to dual phosphotyrosines within immunoreceptor tyrosine-based activation motifs of individual γ chains. In this model, Syk activity is modulated by phosphorylation occurring between adjacent Syk molecules docked on γ homodimers and by Lyn molecules bound to FcεRIβ. However, the mechanistic details of Syk docking on γ homodimers are not fully resolved, particularly the possibility of trans binding orientations and the impact of Y130 autophosphorylation within Syk interdomain A. Analytical modeling shows that multivalent interactions lead to increased WT Syk cis -oriented binding by three orders of magnitude. Molecular dynamics (MD) simulations show increased inter-SH2 flexibility in a Y130E phosphomimetic form of Syk, associated with reduced overall helicity of interdomain A. Hybrid MD/worm-like chain polymer models show that the Y130E substitution reduces cis binding of Syk. We report computational models and estimates of relative binding for all possible cis and trans 2:2 Syk:FcεRIγ complexes. Calcium imaging experiments confirm model predictions that cis binding of WT Syk is strongly preferred for efficient signaling, while trans conformations trigger weak but measurable responses." @default.
- W2901431507 created "2018-11-29" @default.
- W2901431507 creator A5001257836 @default.
- W2901431507 creator A5008472243 @default.
- W2901431507 creator A5016509891 @default.
- W2901431507 creator A5043496898 @default.
- W2901431507 creator A5045407180 @default.
- W2901431507 creator A5063460625 @default.
- W2901431507 creator A5087034992 @default.
- W2901431507 date "2018-11-14" @default.
- W2901431507 modified "2023-10-03" @default.
- W2901431507 title "Molecular aspects of multivalent engagement between Syk and FcεRIγ" @default.
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