Document Detail


Characterization of mutant Bordetella pertussis adenylate cyclase toxins with reduced affinity for calmodulin. Implications for the mechanism of toxin entry into target cells.
MedLine Citation:
PMID:  9057827     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Bordetella pertussis secretes a calmodulin-stimulated adenylate cyclase toxin (CyaA) that is one of the major virulence factors of this organism. The toxin is able to enter various types of eukaryotic cells where, upon activation by calmodulin, it catalyzes the production of non-physiological amounts of cyclic AMP. The mechanism of toxin entry into target cells is unknown, although it has been shown that it does not involve receptor-mediated endocytosis. The adenylate cyclase toxin exhibits a very high affinity for calmodulin, and it has been proposed that the energy of calmodulin-binding to CyaA might be required for the entry of the toxin into the target cells [Oldenburg, D.J., Gross, M. K., Wong, C. S. & Storm, D. R. (1992) Biochemistry 31, 8884-8891]. In the present study, we have reexamined this issue by analyzing the cytotoxicity of various modified CyaA toxins that have altered calmodulin affinity. We show that despite their low affinity for calmodulin (at least 1000-times less than that of the wild type CyaA), these toxins were able to efficiently deliver their catalytic domain into the cytoplasm of the target cells, erythrocytes. These results demonstrate that high-affinity calmodulin binding is not required for the entry of B. pertussis adenylate cyclase into eukaryotic cells. However, the high-affinity of CyaA for calmodulin is crucial for an efficient synthesis of cAMP within the target cells.
Authors:
N Heveker; D Ladant
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of biochemistry / FEBS     Volume:  243     ISSN:  0014-2956     ISO Abbreviation:  Eur. J. Biochem.     Publication Date:  1997 Feb 
Date Detail:
Created Date:  1997-03-26     Completed Date:  1997-03-26     Revised Date:  2007-07-23    
Medline Journal Info:
Nlm Unique ID:  0107600     Medline TA:  Eur J Biochem     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  643-9     Citation Subset:  IM    
Affiliation:
Unité de Biochimie des Régulations Cellulaires, CNRS URA 1129, Paris, France.
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MeSH Terms
Descriptor/Qualifier:
Adenylate Cyclase / blood,  chemistry*,  genetics
Animals
Bacterial Toxins / blood,  chemistry*,  genetics
Bordetella pertussis / enzymology*,  genetics*
Calmodulin / chemistry*
Catalysis
Cyclic AMP / metabolism
Erythrocytes / drug effects,  metabolism*
Mutagenesis, Insertional
Protein Binding
Sheep
Chemical
Reg. No./Substance:
0/Bacterial Toxins; 0/Calmodulin; 60-92-4/Cyclic AMP; EC 4.6.1.1/Adenylate Cyclase

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