picture story

The mitogen-activated protein kinases, orMAP kinases, mediate cellular responsesto extracellular signals by phosphoryla-tion of downstream factors. Members ofthe p38 MAP kinase family are activatedin response to physical and chemicalstresses and are regulated by many differ-ent extracellular signaling molecules,including cytokines, growth factors andneuropeptides. Although more and morestructural data is becoming available forthe MAP kinases, our understanding ofhow a specific pathway is selected duringthe signaling process is complicated by thefact that MAP kinases are notoriouslypromiscuous. A single kinase may beinvolved in multiple signaling cascadesand interact with numerous substratesand activators, as well as scaffolding pro-teins and inactivating enzymes. Under-standing how multiple and diverseproteins interact with p38 and affect p38kinase activity is an area of intense study.

In a recent issue of Molecular Cell(Mol. Cell 9, 1241–1249; 2002), Chang et al.investigate the structural changes in p38MAP kinase that arise upon binding to pep-tides comprising the docking sites of p38substrate MEF2A and activator MKK3b.Comparison (via superposition) of thestructures of p38 with (red) and without(green) the MEF2A peptide revealed someinteresting features. The peptide, shown inpink, binds to p38 in a groove in the C-ter-minal domain. The binding groove is near,though distinct from, the active site (indi-cated by blue arrowhead).

The activator MKK3b peptide binds atthe same site, which is perhaps not unex-

pected. Docking site sequences similar tothose identified in p38 substrates had beenidentified in activating enzymes and MAPkinase scaffolding proteins as well as theinactivating protein tyrosine phosphatases,suggesting similar modes of interactionbetween these diverse proteins and p38.Substrate docking is thought to be impor-tant for determining signaling pathway. Ifactivating enzymes (or inactivatingenzymes or scaffolding proteins) are inter-acting in a similar fashion, how is it thatthey elicit their specific response in p38?From the structures reported by Changet al., it seems that these different responsesmay be linked to conformational changesin the p38 active site and phosphorylationlip (black arrowhead), which differ accord-ing to the identity of the docked protein(or, in this case, peptide).

Both the transcription factor substrateMEF2A peptide and the activating enzyme

MKK3b peptide induce large conforma-tional changes in the binding groove.However, both peptides also induce sepa-rate and distinct changes at the active site,which may have implications in p38 acti-vation. The phosphorylation lip, whichcontains the sites where phosphorylationoccurs during kinase activation, exhibitsperhaps the most significant change onbinding of either peptide. In both cases,peptide binding induces disorder in thephosphorylation lip (signified with adashed line in the MEF2A peptide-boundp38). Although the physiological rele-vance of these conformational changes isso far unclear, Chang et al. suggest that inthe case of MKK3b, binding of the activat-ing enzyme may release this loop for bind-ing into the MKK3b active site allowingfor phosphorylation — and thus activa-tion — of p38.

Elizabeth H. Cox

MAPping p38 binding interactions

nature structural biology • volume 9 number 8 • august 2002 569

©20

02 N

atu

re P

ub

lish

ing

Gro

up

h

ttp

://s

tru

ctb

io.n

atu

re.c

om