Structural basis for autoinhibition of the EphB2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region

The Eph receptor tyrosine kinase family is regulated by autophosphorylation within the juxtamembrane region and the kinase activation segment. We have solved the X-ray crystal structure to 1.9 Angstrom resolution of an autoin hibited, unphosphorylated form of EphB2 comprised of the juxtamembrane regi on and the kinase domain. The structure, supported by mutagenesis data, rev eals that the juxtamembrane segment adopts a helical conformation that dist orts the small lobe of the kinase domain, and blocks the activation segment from attaining an activated conformation. Phosphorylation of conserved jux tamembrane tyrosines would relieve this autoinhibition by disturbing the as sociation of the juxtamembrane segment with the kinase domain, while libera ting phosphotyrosine sites for binding SH2 domains of target proteins. We p ropose that the autoinhibitory mechanism employed by EphB2 is a more genera l device through which receptor tyrosine kinases are controlled.