Structure and Activation of the Tyrosine Kinase Domain

Stimulation of the cytoplasmic localized tyrosine kinase activity is observed as a consequence of binding of the protein ligand to the extracellular side of the receptor tyrosine kinase. 

Autophosphorylation and phosphorylation of substrate proteins are essential elements of signal transduction via receptor tyrosine kinases. Autophosphorylation fre- 

Autophosphorylation may be attributed two functions first, activation of the own Tyr kinase activity by cancelling autoinhibition second, creation of binding sites for corresponding effector proteins, in that Tyr phosphate binds to the SH2 domains or PTB domains (see 8.2) of effector molecules (Fig. 8.6). 

The first insight into the mechanism by which autophosphorylation controls the activity of the Tyr kinase was possible via the crystal structure of the Tyr kinase domain of the human insulin receptor (Hubbard et al., 1994). 

It is assumed that the catalytic domain of the receptor can exist in two conformations. In the inactive conformation, the activation segment lies in the catalytic center, whereas in the active conformation, it swings out of the active center and both the ATP binding site and the binding site for protein substrate are free and accessible. According to this model, the equilibirum of the two conformations lies on the side of the inactive form in the non-phosphorylated state phosphorylation at Tyrll62 shifts it towards the active form. 

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