K. Futterer, J. Wong, R.A. Grucza, A.C. chan, G. Waksman.
Structural basis for Syk tyrosine kinase ubiquity in signal transduction
pathways revealed by the crystal structure of its regulatory SH2 domains bound
to a dually phosphorylated ITAM peptide.
Journal of Molecular Biology. 281:523-537. (1998)
The Syk family of kinases, consisting of
ZAP-70 and Syk, play essential roles in a variety of immune and non-immune
cells. This family of kinases is characterized by the presence of two adjacent
SH2 domains which mediate their localization to the membrane through receptor
encoded tyrosine phosphorylated motifs. While these two kinases share many
structural and functional features, the more ubiquitous nature of Syk has
suggested that this kinase may accommodate a greater variety of motifs to
mediate its function. We present the crystal structure of the tandem SH2 domain
of Syk complexed with a dually phosphorylated ITAM peptide. The structure was
solved by multiple isomorphous replacement at 3.0 resolution. The asymmetric
unit comprises six copies of the liganded protein, revealing a surprising
flexibility in the relative orientation of the two SH2 domains. The C-terminal
phosphotyrosine-binding site is very different from the equivalent region of
ZAP-70, suggesting that in contrast to ZAP-70, the two SH2 domains of Syk can
function as independent units. The conformational flexibility and structural
independence of the SH2 modules of Syk likely provides the molecular basis for
the more ubiquitous involvement of Syk in a variety of signal transduction
pathways.