The Third Conformation of p38α MAP Kinase Observed in Phosphorylated p38α and in Solution

SummaryMAPKs engage substrates, MAP2Ks, and phosphatases via a docking groove in the C-terminal domain of the kinase. Prior crystallographic studies on the unphosphorylated MAPKs p38α and ERK2 defined the docking groove and revealed long-range conformational changes affecting the activation loop and active site of the kinase induced by peptide. Solution NMR data presented here for unphosphorylated p38α with a MEK3b-derived peptide (p38α/pepMEK3b) validate these findings. Crystallograhic data from doubly phosphorylated active p38α (p38α/T∗GY∗/pepMEK3b) reveal a structure similar to unphosphorylated p38α/MEK3b, and distinct from phosphorylated p38γ (p38γ/T∗GY∗) and ERK2 (ERK2/T∗EY∗). The structure supports the idea that MAP kinases adopt three distinct conformations: unphosphorylated, phosphorylated, and a docking peptide-induced form.

Graphical AbstractFigure optionsDownload high-quality image (190 K)Download as PowerPoint slideHighlights
► Docking peptides induce local and long-range changes in p38a observed by solution NMR
► Docking peptides induce similar structures in active and inactive p38α
► The allosteric mechanism of peptide-induced changes involves water molecules