Molecular aspects of multivalent engagement between Syk and FcϵRIγ

摘要: 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 motifs individual γ chains. In this model, activity is modulated by phosphorylation occurring between adjacent molecules docked on homodimers and Lyn bound FcϵRIβ However, mechanistic details docking not fully resolved, particularly possibility trans orientations impact Y130 autophosphorylation interdomain A. Analytical modeling shows multivalent interactions lead increased WT cis-oriented three orders magnitude. Molecular dynamics (MD) simulations show inter-SH2 flexibility in a Y130E phosphomimetic form Syk, associated with reduced overall helicity Hybrid MD/worm-like chain polymer models substitution reduces Syk. We report computational estimates relative all possible 2:2 Syk:FcϵRIγ complexes. Calcium imaging experiments confirm predictions strongly preferred efficient signaling, while conformations trigger weak but measurable responses.