Masking autoprocessing of Clostridium difficile toxin A by the C-terminus combined repetitive oligo peptides.

Authors:
Yongrong Zhang
Yongrong Zhang
Tufts Cummings School of Veterinary Medicine
United States
Therwa Hamza
Therwa Hamza
University of Maryland Dental School
Baltimore | United States
Si Gao
Si Gao
School of Pharmaceutical Sciences
China
Hanping Feng
Hanping Feng
Tufts University Cummings School of Veterinary Medicine
United States

Biochem Biophys Res Commun 2015 Apr 26;459(2):259-263. Epub 2015 Feb 26.

Department of Microbial Pathogenesis, University of Maryland Dental School, Baltimore, MD 21201, USA. Electronic address:

Clostridium difficile toxin A and B (TcdA and TcdB) are the major virulence factors of the bacterium, both of which consist of two enzymatic domains: an effector glucosyltransferase domain (GTD) and a cysteine protease domain (CPD) responsible for autocleavage and release of GTD. Although the CPDs from both toxins share a similar structure and mechanism of hexakisphosphate (InsP6)-induced activation, TcdA is substantially less sensitive to the autocleavage as compared with TcdB. In this study, we provided evidence of inter-domain regulation of CPD activity of TcdA and its autoprocessing. The C-terminus combined repetitive oligo peptides (CROPs) of TcdA reduced the accessibility of TcdB CPD to its substrate in a chimeric toxin TxB-Ar, consequently blocking autoprocessing. Moreover, interference of antibodies with the CROPs of full-length TcdA efficiently enhanced its GTD release. In conclusion, by utilizing chimeric toxins and specific antibodies, we identified that the CROPs of TcdA plays a crucial role in controlling the InsP6-mediated activation of CPD and autocleavage of GTD. Our data provides insights on the molecular mode of action of the C. difficile toxins.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S0006291X150033
Publisher Site
http://dx.doi.org/10.1016/j.bbrc.2015.02.095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426850PMC

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April 2015
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