Date of Award

January 2016

Degree Type


Degree Name

Doctor of Philosophy (PhD)


Medicinal Chemistry and Molecular Pharmacology

First Advisor

Carol B Post

Committee Member 1

Daisuke Kihara

Committee Member 2

Robert Geahlen

Committee Member 3

Nikolai Skrynnikov


Spleen tYrosine Kinase (Syk) is one of the crucial signaling proteins involved in the development of immune cells and the initiation of inflammatory responses. Syk is a 72-kDa kinase comprising three folded domains: two SH2 domains and a catalytic domain. The tandem SH2 domains connected by linker A are key to the regulation of Syk activity. Immune signaling through Syk is initiated by the binding of the tandem SH2 to the dpITAMs found on immune cell receptors. The high-affinity, bifunctional binding of Syk tandem SH2 to the immunoreceptor requires that the two phosphotyrosines (pTyr) of the dpITAM fit the spacing and orientation of the two SH2 domains. Phosphorylation at Y130, which introduces a negative charge in the linker A, disrupts the domain-domain coupling and causes the binding affinity of each SH2 domain to the pTyr of the dpITAM to differ; the optimal binding to dpITAM seen with the unphosphorylated form is therefore no longer possible. Because Y130 is far from the dpITAM binding sites, phosphorylation of Y130, therefore, negatively regulates the association of Syk with immunoreceptors through an allosteric mechanism. In this work, the molecular detail of this allosteric mechanism was investigated using molecular dynamics simulations. The use of μs-trajectories enabled us to define the perturbation caused by Y130 phosphorylation to the domain-domain dynamics and the conformational ensemble of the tandem SH2. A picture in which the Syk-immunoreceptor interaction is regulated by a mechanism of dynamic allostery emerged.