Myxoma Virus Immunomodulatory Protein M156R is a Structural Mimic of Eukaryotic Translation Initiation Factor eIF2α

Phosphorylation of the translation initiation factor eIF2 on Ser51 of its α subunit is a key event for regulation of protein synthesis in all eukaryotes. M156R, the product of the myxoma virus M156R open reading frame, has sequence similarity to eIF2α as well as to a family of viral proteins that bind to the interferon-induced protein kinase PKR and inhibit phosphorylation of eIF2α. In this study, we demonstrate that, like eIF2α. M156R is an efficient substrate for phosphorylation by PKR and can compete with eIF2α. To gain insights into the substrate specificity of the eIF2α kinases, we have determined the nuclear magnetic resonance (NMR) structure of M156R, the first structure of a myxoma virus protein. The fold consists of a five-stranded antiparallel β-barrel with two of the strands connected by a loop and an α-helix. The similarity between M156R and the β-barrel structure in the N terminus of eIF2α suggests that the viral homologs mimic eIF2α structure in order to compete for binding to PKR. A homology-modeled structure of the well-studied vaccinia virus K3L was generated on the basis of alignment with M156R. Comparison of the structures of the K3L model, M156R, and human eIF2α indicated that residues important for binding to PKR are located at conserved positions on the surface of the β-barrel and in the mobile loop, identifying the putative PKR recognition motif.