Date of Award

1-1-2014

Document Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

First Advisor

Scott D. PEgan

Keywords

CCHF, deubiquitination, Dugbe, nairovirus, Ubiquitin, vOTU

Abstract

My research focuses on understanding the substrate specificity of the viral homolog of the ovarian tumor domain protease superfamily (vOTU) from nairoviruses, and the structural reasons for their specificities. The vOTU from the Crimean-Congo Hemorrhagic Fever Virus (CCHFV) has been implicated in the down-regulation of the innate immune response through its ability to cleave post-translational modifications via Ubiquitin (Ub) as well as the Ub-like interferon-stimulated gene 15 (ISG15). vOTU homologs have been found in numerous viruses across several families. Moreover, the effects of these viruses range in severity from mild flu-like symptoms to mortality depending on the species of the infected host. As such, several nairovirus vOTUs including those from the Dugbe Virus (DUGV), Erve Virus (ERVEV), and CCHFV were subjected to enzymological studies to gain insight into substrate specificity. These studies revealed that even vOTUs from the same viral family have differing specificities for Ub and ISG15. Furthermore, these preferences extend to include the different polymeric moieties of Ub. In order to gain insight into any structural reasoning for these substrate predilections, the X-ray crystal structures of the vOTUs from both CCHFV and DUGV were each solved covalently bound with Ub. These structures exposed unique secondary structure elements compared to other members of the OTU superfamily that offer understanding into why certain vOTUs, such as that from CCHFV, can possess robust activity for Ub and ISG15. Likewise, the crystallographic data point to the primary structure of the vOTUs as the main driving force for divergence between nairovirus vOTU specificity.

Provenance

Recieved from ProQuest

Rights holder

Glenn Capodagli

File size

138 p.

File format

application/pdf

Language

en

Discipline

Biophysics

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