"Investigating the vaccinia virus immunomodulator A46:
An integrated structural biology approach”
Editor-in-Chief, Archives of Virology
Max Perutz Labs, Medical University of Vienna
on: Thursday, November 5, 2020, 17:15
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ABSTRACT: Vaccinia virus, the virus used to vaccinate against smallpox virus and so eradicate it, encodes many proteins that lessen the activity of the host immune system. At least ten such proteins encoded by vaccinia virus are known to interfere with intracellular signalling in the immune system. We have been examining the structure and function of the protein A46 by integrating X-ray crystallography, electron microscopy and chemical cross-linking. We could show that the A46 protein has an unusual N-terminal lipid-binding domain compressing entirely of β-strands whereas the C-terminal domain has a Bcl2-like fold comprising entirely of α-helices. Through complex interactions, the protein can exist as a dimer or a tetramer in solution. Previous work had shown that A46 prevents immune signalling by binding to proteins containing toll-like receptor domains such as TLR4, MyD88, MAL, TRAM and TRIF. The studies in the electron microscope revealed that A46 can prevent fiber formation by MAL as well as MyD88 fiber formation induced by MAL. Chemical cross-linking and predictions from the X-ray structure enabled residues on A46 on the one hand and MAL and MyD88 on the other to be identified that are involved in these interactions. The lecture will show how the integration of the three structural biology approaches has vastly increased our understanding of the mechanism of this protein as well as indicating how the problems that were encountered during the project were solved.
Contact: Doctoral Program MolTag; moltag.univie.ac.at, Office.moltag@univie.ac.at
