Spleen tyrosine kinase (Syk) is an essential player in immunity through its ability to couple a variety of membrane immunoreceptors to intracellular signaling pathways in an immune response. Receptor activation leads to the recruitment of Syk to a cytoplasmic region of the receptors called ITAM.  Syk associates with high-affinity (nanomolar <i>K<sub>D</sub></i>) to the receptor ITAM.  A unique phosphorylation mechanism regulates this interaction; phosphorylation of Syk on a tyrosine distant to the binding site causes substantial reduction in affinity by an increased entropy penalty from conformational disorder, without altering SH2-ITAM binding contacts, and binding enthalpy is unchanged.  To begin to understand how phosphorylation triggers disorder without affecting binding interactions, we analyzed molecular dynamics simulations of unphosphorylated and phosphorylated Syk.  Disparate electrostatic networks involving highly conserved charged residues at the domain interfaces have remarkable correlation in dynamics over long distances and appear to be the basis of the regulation. The simulated behavior is consistent with NMR relaxation measurements, giving confidence in the microscopic characterization provided by MD.  We discovered the key factor to be a triad of charged residues that is centrally located between the three domain and anchors both networks.

Syk association with immune receptors, a unique entropy-driven mechanism to regulate protein interactions by phosphorylation

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