Biophysical studies of the allosteric regulatory mechanism of Syk tandem SH2 domains interacting with immunoreceptor tyrosine-based activation motifs

<p>The non-receptor spleen tyrosine kinase (Syk) is an important player in signal transduction from immunoreceptors to various downstream targets. It is widely expressed in both haematopoietic and epithelial cells. Syk disorder is closely related with many inflammatory and autoimmune diseases, as well as cancers.</p> <p>Syk associates with immunoreceptors through its tandem SH2 domains (tSH2), which contain two SH2 domains connected by interdomain A. The association of Syk with immunoreceptors is regulated by Y130 phosphorylation in interdomain A. The unphosphorylated tSH2 can bind with the doubly phosphorylated immunoreceptor tyrosine-based activation motif (dp-ITAM) of the cytoplasmic domains of immunoreceptors with very high affinities (nanomolars for <em>K</em>d). However, when Y130 is phosphorylated, the binding affinities drop drastically (micromolars for <em>K</em>d). Interestingly, Y130 locates far (>20 Å) from the binding sites and the detailed mechanism of this long-distance allosteric regulation is largely unknown.</p> <p>A series of biophysical experiments, such as NMR and ITC, have been done to understand this allosteric mechanism. The results revealed interesting changes in the domain-domain coupling and multistate equilibrium thermodynamics of tSH2-ITAM interaction. These data suggested an entropic-allostery mechanism of Syk release from immunoreceptors. The new knowledge obtained from this work will help to explain the regulatory mechanism of Syk activity, assist the design for new drugs to treat Syk-related disorders, and promote researches of other kinases containing tandem SH2 domains.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Medicinal Chemistry and Molecular Pharmacology

Year

2016

Author dc:creator

• Feng, Chao

Contributors dc:contributor

• Carol B. Post
• Robert L. Geahlen
• Tony R. Hazbun
• Andrew D. Mesecar

• Pure sciences
• Biological sciences
• Immunoreceptor tyrosine-based activation motif
• Isothermal titration calorimetry entropic dynamic allostery
• Multistate equilibrium thermodynamics
• Nuclear magnetic resonance line shape titration curve analysis
• Spleen tyrosine kinase
• Tandem SH2 domains
• Biochemistry
• Bioinformatics
• Biophysics

Repository record dc:identifier

https://docs.lib.purdue.edu/open_access_dissertations/645

OAI identifier oai:identifier

oai:docs.lib.purdue.edu:open_access_dissertations-1762