Signaling by the
epidermal growth factor receptor requires an
allosteric interaction between the
kinase domains of two receptors, whereby one activates the other. We show that the
intracellular juxtamembrane segment of the receptor, known to potentiate
kinase activity, is able to dimerize the
kinase domains. The
C-terminal half of the juxtamembrane segment latches the activated
kinase domain to the activator, and the
N-terminal half of this segment further potentiates dimerization, most likely by forming an antiparallel helical dimer that engages the
transmembrane helices of the activated receptor. Our data are consistent with a mechanism in which the
extracellular domains block the intrinsic ability of the
transmembrane and
cytoplasmic domains to dimerize and activate, with
ligand binding releasing this block. The formation of the activating juxtamembrane latch is prevented by the
C-terminal tails in a structure of an inactive
kinase domain dimer, suggesting how alternative dimers can prevent ligand-independent
activation.
