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Title page for ETD etd-09222009-162538


Type of Document Dissertation
Author Ivie, Susan Elizabeth
URN etd-09222009-162538
Title Structure-function analysis of the Helicobacter pylori VacA p55 domain
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Timothy Cover Committee Chair
Andrew Link Committee Member
Dana B. Lacy Committee Member
Eric Skaar Committee Member
Mark Denison Committee Member
Richard Peek Committee Member
Keywords
  • Helicobacter pylori
  • VacA
  • vacuolating cytotoxin
Date of Defense 2009-09-16
Availability unrestricted
Abstract
Colonization of the human stomach with Helicobacter pylori leads to gastric inflammation and is associated with an increased risk for development of peptic ulceration and gastric cancer. An important H. pylori virulence determinant is a toxin known as VacA. VacA is secreted by an autotransporter pathway, and the secreted VacA protein is comprised of two domains, designated p33 and p55. We have identified specific amino acids within the p55 domain that are essential for assembly of VacA into functional oligomeric complexes, and we show that a VacA mutant protein lacking these amino acids can inhibit the activity of wild-type VacA in a dominant-negative manner. In addition, we show that within a â-helical region of the p55 domain, there are regions of plasticity that tolerate large deletions without detrimental effects on protein secretion or activity, as well as a region that is required for proper folding and secretion of the toxin. These results broaden our understanding of VacA structure-function relationships, and also are relevant to understanding the role of â-helical folds in other bacterial proteins that are secreted by an autotransporter pathway.
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