Date of Award

6-1-2014

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

College of Natual Science and Mathematics

First Advisor

Scott D. Pegan, Ph.D.

Second Advisor

Joseph Angleson

Third Advisor

Martin Margittai

Fourth Advisor

Andrei Kutateladze

Keywords

Crimean-Congo Hemorrhagic Fever Virus (CCHF), Deubiquitination, Dugbe, Nairovirus, Ubiquitin, Ovarian tumor domain protease (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.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Glenn C. Capodagli

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

138 p.

Discipline

Biophysics

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