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

The Syk family of kinases, consisting of ZAP-70 and Syk, play essentia l roles in a variety of immune and non-immune cells. This family of ki nases is characterized by the presence of two adjacent SH2 domains whi ch mediate their localization to the membrane through receptor encoded tyrosine phosphorylated motifs. While these two kinases share many st ructural and functional features, the more ubiquitous nature of Syk ha s suggested that this kinase may accommodate a greater variety of moti fs to mediate its function. We present the crystal structure of the ta ndem SH2 domain of Syk complexed with a dually phosphorylated ITAM pep tide. The structure was solved by multiple isomorphous replacement at 3.0 Angstrom resolution. The asymmetric unit comprises six copies of t he liganded protein, revealing a surprising flexibility in the relativ e orientation of the two SH2 domains. The C-terminal phosphotyrosine-b inding site is very different from the equivalent region of ZAP-70, su ggesting that in contrast to ZAP-70, the two SH2 domains of Syk can fu nction as independent units. The conformational flexibility and struct ural independence of the SH2 modules of Syk likely provides the molecu lar basis for the more ubiquitous involvement of Syk in a variety of s ignal transduction pathways. (C) 1998 Academic Press.