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Homology-based Structural Prediction of the Binding Interface Between the Tick-Borne Encephalitis Virus Restriction Factor TRIM79 and the Flavivirus Non-structural 5 Protein.

Brown, Heather Piehl
http://orcid.org/0000-0002-6946-3754
http://rave.ohiolink.edu/etdc/view?acc_num=mco1481304908426729

Abstract Details

2016, Master of Science in Biomedical Sciences (MSBS), University of Toledo, Biomedical Sciences (Bioinformatics and Proteomics/Genomics).
The innate immune system of the host is vital for determining the outcome of virulent virus infections. Successful immune responses depend on detecting the specific virus, through interactions of the proteins or genomic material of the virus and host factors. We previously identified a host antiviral protein of the tripartite motif (TRIM) family, TRIM79, which plays a critical role in the antiviral response to flaviviruses. The Flavivirus genus includes many arboviruses that are significant human pathogens, such as tick-borne encephalitis virus (TBEV) and West Nile virus (WNV). We found that TRIM79 directly interacts with the viral polymerase, nonstructural protein 5 (NS5), and leads to lysosomal degradation of NS5. This restriction is specific to TBEV, as the direct binding of TRIM79 and subsequent degradation of NS5 was not seen in the mosquito-borne flavivirus WNV, despite the TBEV and WNV NS5 proteins sharing a 59% identity. Thus, dissecting the TRIM79/NS5 interaction will provide an effective model of how antiviral proteins differentiate between similar viral proteins. To begin addressing how TRIM79 targets only TBEV NS5 the 3D structures of TBEV and WNV NS5 were compared and modeled the TBEV NS5/TRIM79 interaction complex to identify critical residues for this interaction. Because the structures of TRIM79 and TBEV NS5 are unsolved, homology-based protein modeling was used to create preliminary structures for both proteins. These structures were then used to predict the binding interface for TRIM79 monomers and dimers. From the predicted binding interfaces, residues important for binding were identified that were unique to TBEV NS5 that could then be mutated to disrupt the interaction, rendering TBEV NS5 resistant to TRIM79 restriction.
R. Travis Taylor, Ph.D. (Committee Chair)
Xiche Hu, Ph.D. (Committee Member)
Robert Blumenthal, Ph.D. (Committee Member)
73 p.
Bioinformatics; Molecular Biology; Virology
TBEV; WNV; homology modeling; molecular mechanics; NS5

Recommended Citations

Citations

  • Brown, H. P. (2016). Homology-based Structural Prediction of the Binding Interface Between the Tick-Borne Encephalitis Virus Restriction Factor TRIM79 and the Flavivirus Non-structural 5 Protein. [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1481304908426729

    APA Style (7th edition)

  • Brown, Heather. Homology-based Structural Prediction of the Binding Interface Between the Tick-Borne Encephalitis Virus Restriction Factor TRIM79 and the Flavivirus Non-structural 5 Protein. 2016. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1481304908426729.

    MLA Style (8th edition)

  • Brown, Heather. "Homology-based Structural Prediction of the Binding Interface Between the Tick-Borne Encephalitis Virus Restriction Factor TRIM79 and the Flavivirus Non-structural 5 Protein." Master's thesis, University of Toledo, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=mco1481304908426729

    Chicago Manual of Style (17th edition)

mco1481304908426729
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© 2016, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.