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

Biochemical and Biophysical Research Communications
Yongrong ZhangHanping Feng

Abstract

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.

References

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Citations

Aug 12, 2016·Nature Microbiology·Nicole M ChumblerD Borden Lacy
May 27, 2017·Critical Reviews in Biochemistry and Molecular Biology·Kathleen E OrrellRoman A Melnyk
Oct 20, 2017·FEMS Microbiology Reviews·Ramyavardhanee Chandrasekaran, D Borden Lacy
Jul 17, 2019·Nature Structural & Molecular Biology·Peng ChenRongsheng Jin
Nov 13, 2018·Frontiers in Microbiology·Soo-Young ChungRalf Gerhard
Aug 31, 2016·Nature Microbiology·Nicole M ChumblerD Borden Lacy
Jun 3, 2021·Microbiology and Molecular Biology Reviews : MMBR·Kathleen E Orrell, Roman A Melnyk
Nov 28, 2021·Nature Reviews. Microbiology·Shannon L KordusD Borden Lacy

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