SH2 domains regulate tyrosine kinase activation. (A) In the autoinhibited state of Src, the SH2 domain recognizes an intramolecular pTyr site (Y572) and stabilizes the inactive kinase. Additional contacts with the SH3 and the SH2-kinase linker promote stabilization of the inactive conformation of Src. Activation of Src, initiated by dephosphorylation of Y527, frees the SH3 and SH2 to recognize other short linear motifs and further promote kinase activity. (B) The Abl tyrosine kinase remains in an inactive conformation analogous to Src but lacks the intramolecular phosphorylation site. Instead, an intramolecular amino-terminal myristolation stabilizes the inactive conformation of Abl. (C) For Abl kinase to be active, it requires the SH2 domain to stabilize the amino lobe of the kinase domain, thereby allowing it to couple pTyr ligand binding and substrate recognition (PDB:1OPL).
