title: Poxvirus A46 protein binds to TIR domain-containing Mal/TIRAP via an α-helical sub-domain.
abstract: Poxviruses are large DNA viruses that replicate in the cytosol and express numerous proteins to subvert the host immunity. Vaccinia virus A46 is a 25kDa protein that antagonizes multiple components of the Toll-like/interleukin-1 receptor (TLR) pathway by targeting cytosolic adaptor proteins. A46 binds to MyD88, Mal/TIRAP, TRIF and TRAM and suppresses the activation of NF-κB and interferon regulatory factors. Each of these cytosolic adaptors has a TIR domain that is critical for oligomerization during signaling. Although the structure of A46 is unknown, it has alternatively been described as an α/β-fold TIR domain, or an all α-helical Bcl-2 fold. Here we provide experimental evidence that the C-terminus of A46 adopts a dimeric α-helical structure, and that this segment retains the ability to interact with monomeric Mal. Furthermore, a peptide fragment of A46 termed VIPER, previously shown to retain the biological properties of the full-length protein, does not interact with Mal in vitro. In summary, we provide for the first time a biophysical analysis of the binding of a poxvirus protein to a TIR domain-containing adaptor molecule.
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Oda
authors.forename: Edward
authors.initials: E
authors.lastname: Franklin
authors.forename: Amir R
authors.initials: AR
authors.lastname: Khan
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017472:Receptors, Interleukin-1 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D013057:Spectrum Analysis; D020349:Surface Plasmon Resonance; D014616:Vaccinia virus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C470409:TICAM1 protein, human; C434984:TIRAP protein, human; D014764:Viral Proteins