The structure of phosphorylated P38γ is monomeric and reveals a conserved activation-loop conformation

AbstractBackground: Mitogen-activated protein (MAP) kinases mediate the cellular response to stimuli such as pro-inflammatory cytokines and environmental stress. P38γ is a new member of the MAP kinase family, and is expressed at its highest levels in skeletal muscle. P38γ is 63% identical in sequence to P38α. The structure of P38α MAP kinase has been determined in the apo, unphosphorylated, inactive form. The structures of apo unphosphorylated ERK2, a related MAP kinase, and apo phosphorylated ERK2 have also been determined.Results: We have determined the structure of doubly phosphorylated P38γ 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. P38γ residue phosphoryl-Thr183 forms hydrogen bonds with five basic amino acids, and these interactions induce an interdomain rotation. The conformation of the activation loop of P38γ is almost identical to that observed in the structure of activated ERK2. However, unlike ERK2, the crystal structure and solution studies indicate that activated P38γ exists as a monomer.Conclusions: Interactions mediated by phosphoryl-Thr183 induce structural changes that direct the domains and active-site residues of P38γ into a conformation consistent with catalytic activity. The conformation of the phosphorylation loop is likely to be similar in all activated MAP kinases, but not all activated MAP kinases form dimers