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Syk tyrosine kinase association with immune receptors is regulated by phosphorylation via a unique entropy-driven mechanism
Add to Calendar 2023-03-01T19:30:00 2023-03-01T20:30:00 UTC Syk tyrosine kinase association with immune receptors is regulated by phosphorylation via a unique entropy-driven mechanism 301A Chemistry Building
Start DateWed, Mar 01, 2023
2:30 PM
to
End DateWed, Mar 01, 2023
3:30 PM
Presented By
Carol Post - Purdue University
Event Series: Chemistry Department Colloquium Seminar Series Spring 2023
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Carol Post

Carol Post - Purdue University

Abstract:

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. Activated immunoreceptors recruit Syk to cytoplasmic regions of the receptor called ITAMs.  Syk associates with high affinity to ITAMs (nanomolar KD) as a result of bifunctional binding involving two SH2 domains of Syk. The binding affinity decreases substantially(micromolar KD) when Syk is modified by phosphorylation on Tyr 130.  The talk will describe NMR and other biophysical data that establish a previously unknown mechanism for regulating protein-protein interactions by phosphorylation.  We find that decreased affinity is the result of a higher entropy penalty due to conformational disorder in unbound Syk, while Syk-ITAM binding contacts are not affected, and binding enthalpy is unchanged.  To begin to understand the molecular basis for how phosphorylation triggers disorder without affecting binding interactions, we used molecular dynamics simulations of unphosphorylated and phosphorylated Syk to characterize conformational equilibrium of interdomain structure of the two forms.  We discovered the unphosphorylated and phosphorylated Syk conformational ensembles comprisedisparate electrostatic networks involving a triad of highly conserved charged residues at the domain interfaces. The number of residues and the lifetime of connectivities of the electrostatic networks differ in a manner consistent with NMR relaxation measurements, giving confidence in the microscopic characterization provided by MD.