Modeling of the Toll‐like receptor 3 and a putative Toll‐like receptor 3 antagonist encoded by the African swine fever virus

• Published in: Protein science Vol. 20; no. 2; pp. 247 - 255
• Main Authors: Henriques, Elsa S., Brito, Rui M. M., Soares, Hugo, Ventura, Sónia, de Oliveira, Vivian L., Parkhouse, R. Michael E.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2011; Wiley Subscription Services, Inc
• Subjects: African swine fever virus; African Swine Fever Virus - chemistry; African Swine Fever Virus - genetics; Amino Acid Sequence; Animals; ASFV; comparative modeling; Computational Biology; immune system; Membrane Proteins; Molecular Dynamics Simulation; Molecular Sequence Data; Protein Folding; Protein Structure, Tertiary; Sequence Alignment; Sequence Analysis, Protein; Sequence Homology, Amino Acid; Signal Transduction; Swine; Toll-Like Receptor 3 - antagonists & inhibitors; Toll-Like Receptor 3 - chemistry; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Toll‐like receptor 3; Viral Proteins - chemistry; Viral Proteins - genetics; Viral Proteins - metabolism
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.554

African swine fever virus (ASFV) is a large double‐stranded DNA virus responsible for a lethal pig disease, to which no vaccine has ever been obtained. Its genome encodes a number of proteins involved in virus survival and transmission in its hosts, in particular proteins that inhibit signaling pathways in infected macrophages and, thus, interfere with the host's innate immune response. A recently identified novel ASFV viral protein (pI329L) was found to inhibit the Toll‐like receptor 3 (TLR3) signaling pathway, TLR3 being a crucial “danger detector.” pI329L has been predicted to be a transmembrane protein containing extracellular putative leucine‐rich repeats similar to TLR3, suggesting that pI329L might act as a TLR3 decoy. To explore this idea, we used comparative modeling and other structure prediction protocols to propose (a) a model for the TLR3–Toll‐interleukin‐1 receptor homodimer and (b) a structural fold for pI329L, detailed at atomistic level for its cytoplasmic domain. As this later domain shares only remote sequence relationships with the available TLR3 templates, a more complex modeling strategy was employed that combines the iterative implementation of (multi)threading/assembly/refinement (I‐TASSER) structural prediction with expertise‐guided posterior refinement. The final pI329L model presents a plausible fold, good structural quality, is consistent with the available experimental data, and it corroborates our hypothesis of pI329L being a TLR3 antagonist.