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Infection and Immunity, July 2008, p. 2843-2851, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.01664-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Helicobacter pylori VacA Subdomain Required for Intracellular Toxin Activity and Assembly of Functional Oligomeric Complexes{triangledown}

Susan E. Ivie,1 Mark S. McClain,2 Victor J. Torres,1 Holly M. Scott Algood,2 D. Borden Lacy,1 Rong Yang,4 Steven R. Blanke,4 and Timothy L. Cover1,2,3*

Department of Microbiology and Immunology,1 Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2605,2 Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212,3 Department of Microbiology and Institute for Genomic Biology, University of Illinois, Urbana, Illinois 618014

Received 13 December 2007/ Returned for modification 17 January 2008/ Accepted 23 April 2008

Helicobacter pylori VacA is a secreted pore-forming toxin that is comprised of two domains, designated p33 and p55. The p55 domain has an important role in the binding of VacA to eukaryotic cell surfaces. A total of 111 residues at the amino terminus of p55 (residues 312 to 422) are essential for the intracellular activity of VacA, which suggests that this region may constitute a subdomain with an activity distinct from cell binding. To investigate the properties of this subdomain, a small deletion mutation (targeting aspartic acid 346 and glycine 347) was introduced into the H. pylori chromosomal vacA gene. Similar to wild-type VacA, the VacA {Delta}346-347 mutant protein was proteolytically processed, secreted, and bound to eukaryotic cells. However, VacA {Delta}346-347 did not cause cell vacuolation or membrane depolarization, and it was impaired in the ability to assemble into large water-soluble oligomeric structures. Interestingly, VacA {Delta}346-347 was able to physically interact with wild-type VacA to form mixed oligomeric complexes, and VacA {Delta}346-347 inhibited wild-type vacuolating activity in a dominant-negative manner. These data indicate that the assembly of functional oligomeric VacA complexes is dependent on specific sequences, including amino acids 346 and 347, within the p55 amino-terminal subdomain.

* Corresponding author. Mailing address: Division of Infectious Diseases, A2200 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 322-2035. Fax: (615) 343-6160. E-mail: timothy.l.cover{at}vanderbilt.edu

{triangledown} Published ahead of print on 28 April 2008.

Editor: B. A. McCormick

Infection and Immunity, July 2008, p. 2843-2851, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.01664-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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