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Title: Structural, Functional, and Immunogenic Insights on Cu,Zn Superoxide Dismutase Pathogenic Virulence Factors from Neisseria meningitidis and Brucella abortus

Abstract

ABSTRACT Bacterial pathogensNeisseria meningitidisandBrucella abortuspose threats to human and animal health worldwide, causing meningococcal disease and brucellosis, respectively. Mortality from acuteN. meningitidisinfections remains high despite antibiotics, and brucellosis presents alimentary and health consequences. Superoxide dismutases are master regulators of reactive oxygen and general pathogenicity factors and are therefore therapeutic targets. Cu,Zn superoxide dismutases (SODs) localized to the periplasm promote survival by detoxifying superoxide radicals generated by major host antimicrobial immune responses. We discovered that passive immunization with an antibody directed atN. meningitidisSOD (NmSOD) was protective in a mouse infection model. To define the relevant atomic details and solution assembly states of this important virulence factor, we report high-resolution and X-ray scattering analyses of NmSOD and of SOD fromB. abortus(BaSOD). The NmSOD structures revealed an auxiliary tetrahedral Cu-binding site bridging the dimer interface; mutational analyses suggested that this metal site contributes to protein stability, with implications for bacterial defense mechanisms. Biochemical and structural analyses informed us about electrostatic substrate guidance, dimer assembly, and an exposed C-terminal epitope in the NmSOD dimer. In contrast, the monomeric BaSOD structure provided insights for extending immunogenic peptide epitopes derived from the protein. These collective results reveal unique contributions of SOD to pathogenic virulence, refine predictivemore » motifs for distinguishing SOD classes, and suggest general targets for antibacterial immune responses. The identified functional contributions, motifs, and targets distinguishing bacterial and eukaryotic SOD assemblies presented here provide a foundation for efforts to develop SOD-specific inhibitors of or vaccines against these harmful pathogens. IMPORTANCEBy protecting microbes against reactive oxygen insults, SODs aid survival of many bacteria within their hosts. Despite the ubiquity and conservation of these key enzymes, notable species-specific differences relevant to pathogenesis remain undefined. To probe mechanisms that govern the functioning ofNeisseria meningitidisandBrucella abortusSODs, we used X-ray structures, enzymology, modeling, and murine infection experiments. We identified virulence determinants common to the two homologs, assembly differences, and a unique metal reservoir within meningococcal SOD that stabilizes the enzyme and may provide a safeguard against copper toxicity. The insights reported here provide a rationale and a basis for SOD-specific drug design and an extension of immunogen design to target two important pathogens that continue to pose global health threats.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1407285
DOE Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
Journal of Bacteriology
Additional Journal Information:
Journal Volume: 197; Journal Issue: 24; Journal ID: ISSN 0021-9193
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY

Citation Formats

Pratt, Ashley J., DiDonato, Michael, Shin, David S., Cabelli, Diane E., Bruns, Cami K., Belzer, Carol A., Gorringe, Andrew R., Langford, Paul R., Tabatabai, Louisa B., Kroll, J. Simon, Tainer, John A., Getzoff, Elizabeth D., and Stock, A. M. Structural, Functional, and Immunogenic Insights on Cu,Zn Superoxide Dismutase Pathogenic Virulence Factors from Neisseria meningitidis and Brucella abortus. United States: N. p., 2015. Web. doi:10.1128/JB.00343-15.
Pratt, Ashley J., DiDonato, Michael, Shin, David S., Cabelli, Diane E., Bruns, Cami K., Belzer, Carol A., Gorringe, Andrew R., Langford, Paul R., Tabatabai, Louisa B., Kroll, J. Simon, Tainer, John A., Getzoff, Elizabeth D., & Stock, A. M. Structural, Functional, and Immunogenic Insights on Cu,Zn Superoxide Dismutase Pathogenic Virulence Factors from Neisseria meningitidis and Brucella abortus. United States. doi:10.1128/JB.00343-15.
Pratt, Ashley J., DiDonato, Michael, Shin, David S., Cabelli, Diane E., Bruns, Cami K., Belzer, Carol A., Gorringe, Andrew R., Langford, Paul R., Tabatabai, Louisa B., Kroll, J. Simon, Tainer, John A., Getzoff, Elizabeth D., and Stock, A. M. Mon . "Structural, Functional, and Immunogenic Insights on Cu,Zn Superoxide Dismutase Pathogenic Virulence Factors from Neisseria meningitidis and Brucella abortus". United States. doi:10.1128/JB.00343-15. https://www.osti.gov/servlets/purl/1407285.
@article{osti_1407285,
title = {Structural, Functional, and Immunogenic Insights on Cu,Zn Superoxide Dismutase Pathogenic Virulence Factors from Neisseria meningitidis and Brucella abortus},
author = {Pratt, Ashley J. and DiDonato, Michael and Shin, David S. and Cabelli, Diane E. and Bruns, Cami K. and Belzer, Carol A. and Gorringe, Andrew R. and Langford, Paul R. and Tabatabai, Louisa B. and Kroll, J. Simon and Tainer, John A. and Getzoff, Elizabeth D. and Stock, A. M.},
abstractNote = {ABSTRACT Bacterial pathogensNeisseria meningitidisandBrucella abortuspose threats to human and animal health worldwide, causing meningococcal disease and brucellosis, respectively. Mortality from acuteN. meningitidisinfections remains high despite antibiotics, and brucellosis presents alimentary and health consequences. Superoxide dismutases are master regulators of reactive oxygen and general pathogenicity factors and are therefore therapeutic targets. Cu,Zn superoxide dismutases (SODs) localized to the periplasm promote survival by detoxifying superoxide radicals generated by major host antimicrobial immune responses. We discovered that passive immunization with an antibody directed atN. meningitidisSOD (NmSOD) was protective in a mouse infection model. To define the relevant atomic details and solution assembly states of this important virulence factor, we report high-resolution and X-ray scattering analyses of NmSOD and of SOD fromB. abortus(BaSOD). The NmSOD structures revealed an auxiliary tetrahedral Cu-binding site bridging the dimer interface; mutational analyses suggested that this metal site contributes to protein stability, with implications for bacterial defense mechanisms. Biochemical and structural analyses informed us about electrostatic substrate guidance, dimer assembly, and an exposed C-terminal epitope in the NmSOD dimer. In contrast, the monomeric BaSOD structure provided insights for extending immunogenic peptide epitopes derived from the protein. These collective results reveal unique contributions of SOD to pathogenic virulence, refine predictive motifs for distinguishing SOD classes, and suggest general targets for antibacterial immune responses. The identified functional contributions, motifs, and targets distinguishing bacterial and eukaryotic SOD assemblies presented here provide a foundation for efforts to develop SOD-specific inhibitors of or vaccines against these harmful pathogens. IMPORTANCEBy protecting microbes against reactive oxygen insults, SODs aid survival of many bacteria within their hosts. Despite the ubiquity and conservation of these key enzymes, notable species-specific differences relevant to pathogenesis remain undefined. To probe mechanisms that govern the functioning ofNeisseria meningitidisandBrucella abortusSODs, we used X-ray structures, enzymology, modeling, and murine infection experiments. We identified virulence determinants common to the two homologs, assembly differences, and a unique metal reservoir within meningococcal SOD that stabilizes the enzyme and may provide a safeguard against copper toxicity. The insights reported here provide a rationale and a basis for SOD-specific drug design and an extension of immunogen design to target two important pathogens that continue to pose global health threats.},
doi = {10.1128/JB.00343-15},
journal = {Journal of Bacteriology},
issn = {0021-9193},
number = 24,
volume = 197,
place = {United States},
year = {2015},
month = {10}
}

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Evolutionary constraints for dimer formation in prokaryotic Cu,Zn superoxide dismutase 1 1Edited by R. Huber
journal, January 1999

  • Bordo, Domenico; Matak, Dijana; Djinovic-Carugo, Kristina
  • Journal of Molecular Biology, Vol. 285, Issue 1
  • DOI: 10.1006/jmbi.1998.2267

Reconciling the chemistry and biology of reactive oxygen species
journal, April 2008


Microbial metalloproteomes are largely uncharacterized
journal, July 2010

  • Cvetkovic, Aleksandar; Menon, Angeli Lal; Thorgersen, Michael P.
  • Nature, Vol. 466, Issue 7307
  • DOI: 10.1038/nature09265

Neisseria meningitidis factor H-binding protein fHbp: a key virulence factor and vaccine antigen
journal, February 2015