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The mechanism of allosteric activation of SYK kinase derived from multiple phospho-ITAM-bound structures
Structure 2024
William J. Bradshaw; Gemma Harris; Opher Gileadi; Vittorio L. Katis
This study determined crystal structures of the SYK kinase tandem SH2 (tSH2) domains alone and bound to three phospho-ITAM (pITAM) peptides, and combined them with SAXS, TR-FRET and mutagenesis to reveal how pITAM binding allosterically activates SYK by releasing its kinase domain. Flow Induced Dispersion Analysis (FIDA) was one of several biophysical methods used, employed on a Fida 1 instrument to measure the hydrodynamic radius (Rh) of full-length SYK in solution. FIDA showed apo SYK had an Rh of 34.2 Å, which increased significantly upon binding pITAMs from FCER1G, CD3G or TYROBP. This measured expansion supported the model that pITAM engagement dissociates the kinase domain from the tSH2 domains.
