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Greater than the sum of its parts: understanding alphavirus infection through characterization of nonstructural polyproteins
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Yost, Samantha Alexis. Greater than the sum of its parts: understanding alphavirus infection through characterization of nonstructural polyproteins. Retrieved from https://doi.org/doi:10.7282/T38C9ZF6

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TitleGreater than the sum of its parts: understanding alphavirus infection through characterization of nonstructural polyproteins
NameYost, Samantha Alexis (author); Marcotrigiano, Joseph (chair); Hampsey, Michael (internal member); Patel, Smita (internal member); Nanda, Vikas (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2016
Other Date2016-05 (degree)
SubjectMicrobiology and Molecular Genetics, Virology
Extent1 online resource (xiv, 112 p. : ill.)
DescriptionAlphaviruses are enveloped, positive strand RNA viruses that are capable of causing a variety of symptoms including arthritis, encephalitis, and even death in humans. Chikungunya virus, a member of the alphavirus genus, is a recently emerging pathogen in the Americas with over one million suspected cases in the Americas in 2014. There is no specific anti-viral treatment or vaccine against any member of the alphavirus genus. The viral nonstructural proteins (nsP1-4) responsible for viral RNA replication are produced as a polyprotein. RNA replication complex template usage is regulated by proteolytic processing of the nonstructural polyproteins. Information about the rearrangement of viral proteins before and after cleavage is essential to understanding of the progression of viral pathogenesis. After cleavage, the mature nsPs each assume individual functions in the RNA replication complex or elsewhere for productive infection. We described a portion of alphavirus polyprotein P23 from Sindbis virus and chikungunya virus. The structures show four domains each occupying a vertex of a rectangle. A 40 Å distance between the nsP2 protease and P2/3 cleavage site supports the proposed trans cleavage mechanism. Our P23 structure was used for ligand docking and will be a useful tool in the development of unique anti-viral therapies. Thus far, nsP3 is the least understood alphavirus protein. In the polyprotein, nsP3 forms an extended linker, encircling nsP2, connecting its two domains, important in efficient polyprotein processing and the progression of infection. The P23 structure also revealed a novel zinc binding domain of nsP3 necessary for viral infection. Further biochemical study indicates a role for nsP3 in regulating nsP2 ATP hydrolysis activity. Additionally, nsP3 macrodomain has been shown to bind ADP-ribose but the significance of this during infection is unknown. Abolishing ADP-ribose binding has a significant negative effect on replication in insect cells, whereas previously only the nsP3 C-terminal region was known to mediate infection in various host cells. Overall, our strategy of describing alphavirus nsPs with regard to their structure and activities pre- and post-cleavage via biophysical, biochemical, and virological methods has significantly contributed to a better understanding of viral pathogenesis and present opportunities for novel anti-viral therapy design.
NotePh.D.
NoteIncludes bibliographical references
Noteby Samantha Alexis Yost
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T38C9ZF6
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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