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Figure 7.
Figure 7. A Model for Src Activation(a) The restrained
conformation of c-Src is stabilized by intramolecular
interactions among the kinase domain, the SH2/SH3 domains, and
the phosphorylated C-terminal tail. In this state, an inhibitory
conformation of the activation loop helps disrupt the kinase
active site by stabilizing a displacement of the C helix. The
formation of the A loop helix, which interferes with substrate
binding and protects Tyr-416 from phosphorylation, relies on a
particular register of the two kinase lobes.(b) Displacement of
SH2 and/or SH3 domains, either by C-terminal tail
dephosphorylation or by competitive binding of optimal SH2/SH3
domain ligands, allows the kinase domain to open, disrupting the
A loop helix and exposing Tyr-416 to phosphorylation.(c)
Phosphorylation of Tyr-416 initiates a conformational
reorganization of the whole activation loop, relieving the
steric barrier for substrate binding, allowing the C-terminal
helix to move back into the active site, and reconstituting a
fully active tyrosine kinase.
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