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Poxvirus A46 protein binds to TIR domain-containing Mal/TIRAP via an α-helical sub-domain

Authors
Journal
Molecular Immunology
0161-5890
Publisher
Elsevier
Volume
48
Identifiers
DOI: 10.1016/j.molimm.2011.07.014
Keywords
  • Vaccinia Virus Protein A46
  • Myd88 Adaptor-Like
  • Innate Immune Signaling
  • Viral Immune Evasion
  • Toll-Like/Interleukin-1 Receptor (Tir) Domain
Disciplines
  • Biology
  • Physics

Abstract

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.

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