Myxoma virus immunomodulatory protein M156R is a structural mimic of eukaryotic translation initiation factor eIF2alpha.
Phosphorylation of the translation initiation factor eIF2 on Ser51 of its alpha 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 eIF2alpha as well as to a family of viral proteins that bind to the interferon-induced protein kinase PKR and inhibit phosphorylation of eIF2alpha. In this study, we demonstrate that, like eIF2alpha. M156R is an efficient substrate for phosphorylation by PKR and can compete with eIF2alpha. To gain insights into the substrate specificity of the eIF2alpha 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 beta-barrel with two of the strands connected by a loop and an alpha-helix. The similarity between M156R and the beta-barrel structure in the N terminus of eIF2alpha suggests that the viral homologs mimic eIF2alpha 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 eIF2alpha indicated that residues important for binding to PKR are located at conserved positions on the surface of the beta-barrel and in the mobile loop, identifying the putative PKR recognition motif.
D000595:Amino Acid Sequence; D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009233:Myxoma virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D014764:Viral Proteins; D019892:eIF-2 Kinase