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Myxoma virus immunomodulatory protein M156R is a structural mimic of eukaryotic translation initiation factor
Theresa A Ramelot1, John R Cort, Adelinda A Yee
1Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
Abstract:
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.
Insights
Myxoma virus protein M156R mimics eukaryotic translation initiation factor 2 alpha subunit (eIF2alpha) by adopting a similar structure. This allows M156R to compete with eIF2alpha for binding to protein kinase PKR, inhibiting protein synthesis regulation.
Area of Science:
- Biochemistry
- Structural Biology
- Virology
Background:
- Phosphorylation of eukaryotic translation initiation factor 2 alpha subunit (eIF2alpha) at Ser51 regulates protein synthesis.
- Viral proteins can interfere with eIF2alpha phosphorylation by binding to protein kinase PKR (PKR).
Purpose of the Study:
- To investigate the mechanism by which myxoma virus protein M156R interacts with PKR.
- To elucidate the structural basis for M156R's inhibition of eIF2alpha phosphorylation.
Main Methods:
- Nuclear magnetic resonance (NMR) structure determination of M156R.
- Homology modeling of vaccinia virus K3L.
- Structural comparison of M156R, K3L, and human eIF2alpha.
Main Results:
- M156R is phosphorylated by PKR and competes with eIF2alpha.
- The NMR structure of M156R reveals a beta-barrel fold similar to eIF2alpha.
- Structural comparison identified conserved residues and a putative PKR recognition motif.
Conclusions:
- Myxoma virus M156R mimics eIF2alpha structure to inhibit PKR.
- The study provides structural insights into viral mimicry of host factors.
- Identified key residues for PKR recognition and inhibition of protein synthesis.