The structure of phosphorylated P38 gamma is monomeric and reveals a conserved activation-loop conformation

Background: Mitogen-activated protein (MAP) kinases mediate the cellular re sponse to stimuli such as pro-inflammatory cytokines and environmental stre ss. P38 gamma is a new member of the MAP kinase family, and is expressed at its highest levels in skeletal muscle. P38 gamma is 63% identical in seque nce to P38 alpha. The structure of P38 alpha MAP kinase has been determined in the ape, unphosphorylated, inactive form. The structures of apo unphosp horylated ERK2, a related MAP kinase, and apo phosphorylated ERK2 have also been determined. Results: We have determined the structure of doubly phosphorylated P38 gamm a in complex with an ATP analog by X-ray crystallography. This is the first report of a structure of an activated kinase in the P38 subfamily, and the first bound to a nucleotide. P38 gamma residue phosphoryl-Thr183 forms hyd rogen bonds with five basic amino acids, and these interactions induce an i nterdomain rotation. The conformation of the activation loop of P38 gamma i s almost identical to that observed in the structure of activated ERK2. How ever, unlike ERK2, the crystal structure and solution studies indicate that activated P38 gamma exists as a monomer. Conclusions: Interactions mediated by phosphoryl-Thr183 induce structural c hanges that direct the domains and active-site residues of P38 gamma into a conformation consistent with catalytic activity. The conformation of the p hosphorylation loop is likely to be similar in all activated MAP kinases, b ut not all activated MAP kinases form dimers.