Crystal structure of the P38α-MAPKAP kinase 2 heterodimer

Abstract

The p38 signaling pathway is activated in response to cell stress and induces production of proinflammatory cytokines. P38α is phosphorylated and activated in response to cell stress by MKK3 and MKK6 and in turn phosphorylates a number of substrates, including MAPKAP kinase 2 (MK2). We have determined the crystal structure of the unphosphorylated p38α-MK2 heterodimer. The C-terminal regulatory domain of MK2 binds in the docking groove of p38α, and the ATP-binding sites of both kinases are at the heterodimer interface. The conformation suggests an extra mechanism in addition to the regulation of the p38α and MK2 phosphorylation states that prevents phosphorylation of substrates in the absence of cell stress. Addition of constitutively active MKK6-DD results in rapid phosphorylation of the p38α-MK2 heterodimer. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.