Structural Basis of Type-I Interferon Sequestration by a Poxvirus Decoy Receptor

Date of Award

Spring 5-15-2011

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



All viruses have evolved mechanisms to evade the host immune system in order to survive and propagate. Interferons provide a common target for viruses as they signal the production of numerous antiviral effectors and provide an important link between innate and adaptive immunity. While most viruses target the intracellular effectors of interferons, orthopoxviruses are unique in that they additionally encode for interferon decoy receptors that act extracellularly.

EVM166 is a secreted decoy receptor encoded by Ectromelia virus able to bind Type-I interferons (IFNs) across several species. To gain further insight into the molecular mechanism by which EVM166 and its orthologues function, we have determined the crystal structure of EVM166 in complex with mIFNα5 at 2.1 Å resolution. The crystal structure shows EVM166 comprising three immunoglobulin (Ig) domains that adopt a “horseshoe” fold that wraps around mIFNα5, masking large portions of mIFNα5’s exposed surface area and concealing regions important for Type-I IFN interaction with both IFNAR1 and IFNAR2.

The impressive contact area made between EVM166 and mIFNα5 is consistent with surface plasmon resonance studies showing sub-nanomolar affinity and a long halflife between the two proteins. Mutational studies of EVM166 suggest this long half-life is dependent on the presence of the C-terminal Ig and that in its absence, EVM166 cannot efficiently compete with the cellular receptors, IFNAR1/IFNAR2. A similar line of reasoning helps explain why, although EVM166 can bind mIFN, it is unable to inhibit its antiviral effects.

Structural analysis and experimental evidence support the presence of glycosaminoglycan (GAG)-binding motifs within the first Ig domain, demonstrating that EVM166 binds to cell surfaces in a GAG-dependent manner. These observations help clarify the unique phenotype of the EVM166 C-terminal Ig truncation mutant (D12). In the absence of exogenous IFN, D12 is able to indirectly cause the phosphorylation of Stat1, a signaling component immediately downstream of IFNAR activation. We believe that D12 is concentrating IFN at the surface of the cell, effectively lowering the minimum concentration of IFN required to signal. This result has an intriguing clinical correlate seen in effective poxvirus vaccines and studies are underway to further investigate this phenomenon.


English (en)

Chair and Committee

David Fremont

Committee Members

Michael Diamond, Michael Holtzman, Deborarh Lenschow, Kenneth Murphy, Robert Schreiber, Niraj Tolia


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