期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 33, 页码 21934-21940出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.018929
关键词
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资金
- National Institutes of Health [RO1 GM075156]
- Cellular and Molecular Microbiology Training
- Germs and Defense Summer Science Academy
- Vanderbilt University Medical Center development
- United States Department of Energy
- Office of Science
- Office of Basic Energy Sciences [DE-AC02-06CH11357]
The action of Clostridium difficile toxins A and B depends on inactivation of host small G-proteins by glucosylation. Cellular inositol hexakisphosphate (InsP6) induces an autocatalytic cleavage of the toxins, releasing an N-terminal glucosyltransferase domain into the host cell cytosol. We have defined the cysteine protease domain (CPD) responsible for autoprocessing within toxin A (TcdA) and report the 1.6 angstrom x-ray crystal structure of the domain bound to InsP6. InsP6 is bound in a highly basic pocket that is separated from an unusual active site by a beta-flap structure. Functional studies confirm an intramolecular mechanism of cleavage and highlight specific residues required for InsP6-induced TcdA processing. Analysis of the structural and functional data in the context of sequences from similar and diverse origins highlights a C-terminal extension and a pi-cation interaction within the beta-flap that appear to be unique among the large clostridial cytotoxins.
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