Vaccinia Virus Immunomodulator A46: Destructive Interactions with MAL and MyD88 Shown by Negative-Stain Electron Microscopy
| Autor: | Meryl Haas, Daniel F. Azar, Andrew Hedger, Tim Skern, Md. Habibur Rahaman, Sofiya Fedosyuk, Bostjan Kobe |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Protein family
Mutagenesis (molecular biology technique) Protein–protein interaction 03 medical and health sciences chemistry.chemical_compound Viral Proteins Structural Biology parasitic diseases Humans Molecular Biology 030304 developmental biology 0303 health sciences Innate immune system Binding Sites Chemistry Myelin and Lymphocyte-Associated Proteolipid Proteins 030302 biochemistry & molecular biology Signal transducing adaptor protein Negative stain Cell biology Molecular Docking Simulation Microscopy Electron TRIF Mutagenesis Myeloid Differentiation Factor 88 Vaccinia Protein Binding |
| Zdroj: | Structure (London, England : 1993). 28(12) |
| ISSN: | 1878-4186 |
| Popis: | Vaccinia virus A46 is an anti-inflammatory and non-anti-apoptotic, two-domain member of the poxviral Bcl-2-like protein family that inhibits the cellular innate immune response at the level of the Toll/interleukin-1 receptor (TIR) domain-containing TLR adaptor proteins MAL, MyD88, TRAM, and TRIF. The mechanism of interaction of A46 with its targets has remained unclear. The TIR domains of MAL and MyD88 have been shown to signal by forming filamentous assemblies. We show a clear concentration-dependent destruction of both of these assemblies by A46 by means of negative-stain electron microscopy from molar ratios of 1:15 for MAL and 1:30 for MyD88. Using targeted mutagenesis and protein-protein crosslinking, we show that A46 interacts with MAL and MyD88 through several facets, including residues on helices α1 and α7 and the C-terminal flexible region. We propose a model in which A46 targets the MAL and MyD88 signalosome intra-strand interfaces and gradually destroys their assemblies in a concentration-dependent manner. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|