The mitogen-activated protein kinases, or MAP kinases, mediate cellular
responses to extracellular signals by phosphorylation of downstream factors.
Members of the p38 MAP kinase family are activated in response to physical and
chemical stresses and are regulated by many different extracellular signaling
molecules, including cytokines, growth factors and neuropeptides. Although more
and more structural data is becoming available for the MAP kinases, our
understanding of how a specific pathway is selected during the signaling
process is complicated by the fact that MAP kinases are notoriously
promiscuous. A single kinase may be involved in multiple signaling cascades and
interact with numerous substrates and activators, as well as scaffolding
proteins and inactivating enzymes. Understanding how multiple and diverse
proteins interact with p38 and affect p38 kinase activity is an area of intense
study.
In a recent issue of Molecular Cell (Mol.
Cell9, 1241−1249;
2002), Chang et al. investigate the
structural changes in p38 MAP kinase that arise upon binding to peptides
comprising the docking sites of p38 substrate MEF2A and activator MKK3b.
Comparison (via superposition) of the structures of p38 with (red) and
without (green) the MEF2A peptide revealed some interesting features. The
peptide, shown in pink, binds to p38 in a groove in the C-terminal domain. The
binding groove is near, though distinct from, the active site (indicated by
blue arrowhead).
The activator MKK3b peptide binds at the same site, which is perhaps not
unexpected. Docking site sequences similar to those identified in p38
substrates had been identified in activating enzymes and MAP kinase scaffolding
proteins as well as the inactivating protein tyrosine phosphatases, suggesting
similar modes of interaction between these diverse proteins and p38. Substrate
docking is thought to be important for determining signaling pathway. If
activating enzymes (or inactivating enzymes or scaffolding proteins) are
interacting in a similar fashion, how is it that they elicit their specific
response in p38? From the structures reported by Chang et al., it seems
that these different responses may be linked to conformational changes in the
p38 active site and phosphorylation lip (black arrowhead), which differ
according to the identity of the docked protein (or, in this case,
peptide).
Both the transcription factor substrate MEF2A peptide and the activating
enzyme MKK3b peptide induce large conformational changes in the binding groove.
However, both peptides also induce separate and distinct changes at the active
site, which may have implications in p38 activation. The phosphorylation lip,
which contains the sites where phosphorylation occurs during kinase activation,
exhibits perhaps the most significant change on binding of either peptide. In
both cases, peptide binding induces disorder in the phosphorylation lip
(signified with a dashed line in the MEF2A peptide-bound p38). Although the
physiological relevance of these conformational changes is so far unclear,
Chang et al. suggest that in the case of MKK3b, binding of the
activating enzyme may release this loop for binding into the MKK3b active site
allowing for phosphorylation — and thus activation — of p38.
