Intrinsic Toxin-Derived Peptides Destabilize and InactivateClostridium difficile TcdB

MBio
Jason L LarabeeJimmy D Ballard

Abstract

Clostridium difficile infection (CDI) is a major cause of hospital-associated, antibiotic-induced diarrhea, which is largely mediated by the production of two large multidomain clostridial toxins, TcdA and TcdB. Both toxins coordinate the action of specific domains to bind receptors, enter cells, and deliver a catalytic fragment into the cytosol. This results in GTPase inactivation, actin disassembly, and cytotoxicity. TcdB in particular has been shown to encode a region covering amino acids 1753 to 1851 that affects epitope exposure and cytotoxicity. Surprisingly, studies here show that several peptides derived from this region, which share the consensus sequence1769NVFKGNTISDK1779, protect cells from the action of TcdB. One peptide, PepB2, forms multiple interactions with the carboxy-terminal region of TcdB, destabilizes TcdB structure, and disrupts cell binding. We further show that these effects require PepB2 to form a higher-order polymeric complex, a process that requires the central GN amino acid pair. These data suggest that TcdB1769-1779interacts with repeat sequences in the proximal carboxy-terminal domain of TcdB (i.e., the CROP domain) to alter the conformation of TcdB. Furthermore, these studies provide insights in...Continue Reading

References

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Citations

Mar 2, 2019·Journal of Biological Engineering·Eric Krueger, Angela C Brown
Nov 13, 2018·Frontiers in Microbiology·Soo-Young ChungRalf Gerhard
Dec 17, 2017·The Journal of Biological Chemistry·Jason L LarabeeJimmy D Ballard
Nov 28, 2021·Nature Reviews. Microbiology·Shannon L KordusD Borden Lacy

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Methods Mentioned

BETA
GTPases
X-ray
glucosylation
surface plasmon resonance
chip
circular dichroism
phage display
PCR

Software Mentioned

GenScript

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