Spleen Tyrosine Kinase (SYK) is an important part of various cellular signalling pathways. The protein possesses N-terminal tandem SH2 domains (tSH2) connected by a helical linker and a C-terminal kinase domain. The kinase domain binds to the tSH2 domains, locking in it an inactive conformation. It was known that the protein becomes active when the tSH2 domains bind to the two phosphorylated YXXL motifs (ITAM) in the tail of a variety of receptor proteins, but how this activation is achieved was unclear.
A recent publication from researchers at the CMD and the Research Complex at Harwell has shed light on the mechanism of activation. The work reports an apo structure and three peptide-bound structures of the tSH2 domains of SYK. Each structure possesses multiple copies of the protein in the asymmetric unit, demonstrating the conformational diversity of the tSH2 domains. A comparison of these structures shows that, upon ITAM binding, the tSH2 domains rotate and are locked into a considerably more rigid conformation. This conformation appears to be incompatible with binding to the kinase domain, causing its release and activation through an allosteric mechanism.
The work was supported by a mutagenesis study looking into ITAM binding, small angle X-ray scattering (SAXS), which demonstrated the change in tSH2 conformational flexibility in solution, and flow-induced dispersion analysis (FIDA), which showed the release of the kinase domain upon ITAM binding.
https://doi.org/10.1016/j.str.2024.09.024
