Date of Award

12-2008

Document Type

Thesis

Degree Name

Master of Science (MS)

Program

Biomedical Sciences

Research Advisor

Charles J. Russell, Ph.D.

Committee

Anjaparavanda Naren, Ph.D. Michael Whitt, Ph.D.

Keywords

hPIV3, F protein, paramyxovirus

Abstract

Paramyxoviruses include a number of important human pathogens, including measles virus, mumps virus, and the human parainfluenza viruses (hPIV) 1-4, as well as several animal pathogens, such as Sendai virus, Nipah virus and Hendra virus. The creation of effective drugs and vaccines against this family of viruses would play an important role in decreasing the prevalence of these viruses and contributing to the health of both humans and animals worldwide. The purpose of this work was to determine how the fusion (F) protein is regulated with a focus on the heptad repeat B (HRB) region of the F protein located in the ectodomain, directly adjacent to the transmembrane domain. This region has been suggested to play important roles in the initiation of fusion

(Gravel 2003) as well as in the formation of the final hairpin structure that drives fusion (Russell 2001). My investigation of the HRB region of the parainfluenza fusion (F) protein has been to characterize the structure of this domain in the pre-fusion form of the F protein in order to better understand the role it plays in fusion. An understanding of how F protein conformational changes are regulated may lead to the creation of more effective therapies against paramyxoviruses in general. A crystal structure obtained from the pre-fusion PIV5 F protein (Yin 2006) reveals that the HRB domain is in a triple stranded coiled coil conformation. However, in order to obtain the structure, a trimerization domain was used for structure stabilization. It is not known if the trimerization domain influenced the resulting crystal structure. My research has investigated the structure of the HRB region by creating mutations in both the pre-fusion hPIV3 F protein and peptides derived from the HRB region. Although much work still remains, preliminary results are consistent with the HRB region of the hPIV3 F protein forming a triple stranded coiled coil in the pre-fusion conformation.

DOI

10.21007/etd.cghs.2008.0047

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