Editors' ChoiceReceptor Activation

Juxtamembrane Interferes with Kinase Activation

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Science's STKE  02 Oct 2001:
Vol. 2001, Issue 102, pp. tw357
DOI: 10.1126/stke.2001.102.tw357

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]

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