Graduate Thesis Or Dissertation
 

Characterization of vaccinia virus A12L protein : its proteolysis and functional analyses in virus replication

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  • In order to produce infectious virus progeny, vaccinia virus (VV) undergoes morphogenic proteolysis to regulate the structural rearrangements of virus particles. Several of the major structural precursor proteins of VV are cleaved at a conserved Ala-Gly-X (where X is any amino acid) motif by the VV I7L core protein proteinase at a step, which is necessary for formation of mature virus particles. VV A12L encodes a 25kDa core protein, which is cleaved at an AG/A site, yielding a 17kDa cleavage product. Both A12L precursor and the cleavage product are localized to mature virions. The open reading frame (ORF) of A12L contains two more AG/X (AG/K) sites, however, cleavage at these sites has not been analyzed. Therefore, the aim of this study is to characterize the in vivo processing of A12L proteolysis and elucidate the biological function of A12L. The result of these studies would provide more details on the regulation and participation of VV proteolysis during the morphogenic transitions. Proteolytic processing of A12L produces multiple peptides, which do not appear to utilize AG/K sites, but rather cleavages occur at both the N- and Cterminus. Of the three AG/X motifs in A12L, cleavage has only been demonstrated at the AG/A site. The enzyme responsible for this cleavage has been shown to be I7L. Immunoprecipitation studies have shown that A12L associates with VV core and membrane proteins. A conditional mutant virus of A12L was constructed and determined the essentiality of A12L in virus replication and helped to elucidate its functions in the assembly of virus particles. An AG/A site mutation abrogated the ability of the transfected A12L gene to rescue the conditional mutant under non-permissive conditions, indicating that its proteolysis at the AG/A site is required during viral replication. Next, we compared the protein expression of A12L with D13L, an internal scaffolding protein, to investigate the role of A12L in virus assembly. We showed that A12L is stably synthesized only in the presence of D13L. Consequently, we established that A12L protein and its proteolysis participate in viral assembly subsequent to D13L involvement.
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