Our laboratory employs biochemical and structural methods (primarily X-ray crystallography) to define the molecular interactions that underlie cytoplasmic signal transduction.
Many cell-surface receptors signal through cytoplasmic tyrosine kinase domains. Activation of receptor and non-receptor kinases initiates a network of interactions among cytoplasmic signalling proteins and ultimately alters cellular physiology and gene expression. A number of modular domains, including Src homology-2 (SH2), Src homology-3 (SH3), pleckstrin homology (PH), and phosphotyrosine binding (PTB) domains, are found in these signalling proteins, and mediate interactions among them. These domains regulate enzyme-substrate recogniton, sub-cellular localization, and the enzymatic activity of associated catalytic domains.
We are particularly interested in the cytoplasmic proteins that control T-cell activation, including the Src-family kinase p56Lck and Zap-70. In our structural studies of these molecules and their component domains, alone and in multi-molecular complexes, we address the following general themes: (1) How is specificity achieved in molecular recognition? (2) How do these modular domains regulate their associated catalytic subunits? (3) How does phosphorylation regulate the activity and interactions of these molecules? and (4) How can our structural results be used for drug design or to develop reagents that will allow further dissection of regulatory pathways?
Selected References:
Eck, M. J., Dhe-Paganon, S., Trub, T., Nolte, R. T., and Shoelson,
S. E. 1996. Structure of the IRS-1 PTB domain bound to the juxtamembrane
region of the insulin receptor. Cell 85, 695-705.
Xu, W., Harrison, S. C., and Eck, M. J. 1997. Three-dimensional structure of the tyrosine kinase c-Src. Nature 385, 595-602.
Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M., and Shoelson, S. 1998. Crystal Structure of the Tyrosine Phosphatase SHP-2. Cell 92:441-450.