Receptor Activation Juxtamembrane Interferes with Kinase Activation

To prevent unregulated activation, kinases have evolved different means to inhibit their intrinsic enzymatic capability. By examining the crystal structure of the EphB2 tyrosine receptor kinase, Wybenga-Groot et al. have identified the mechanism by which the kinase regulates its own activation. The juxtamembrane segment (on the cytoplasmic side) of unphosphorylated EphB2 adopts an α-helical structure that interferes with kinase activation. ATP binding to the receptor is not inhibited; rather, the α helix interferes with the movement of the kinase's activation loop to a position that favors activation. On the other hand, the authors suggest that apposition of the α helix and the kinase domain would prevent the phosphorylation of the tyrosines (known to be docking sites for signaling proteins) that reside in the α helix. Phosphorylation of two tyrosines in the juxtamembrane segment would cause the separation of the α-helical segment from the activation loop, freeing the catalytic domain for activation. Thus, the data suggest that EphB2 utilizes a mechanism whereby its kinase activity and its essential docking-site tyrosine residues are inaccessible until the proper stimulatory signals are present.

L. E. Wybenga-Groot, B. Baskin, S. H. Ong, J. Tong, T. Pawson, F. Sicheri, Structural basis for autoinhibition of the EphB2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 106, 745-757 (2001). [Full Text]