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J Biol Chem. 2009 Aug 14;284(33):21934-40. doi: 10.1074/jbc.M109.018929. Epub 2009 Jun 24.

Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A.

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  • 1Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232-2363, USA.

Abstract

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 A 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.

PMID:
19553670
PMCID:
PMC2755918
DOI:
10.1074/jbc.M109.018929
[PubMed - indexed for MEDLINE]
Free PMC Article
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