Quercetin-3-Rutinoside Blocks the Disassembly of Cholera Toxin by Protein Disulfide Isomerase

Toxins

Michael Taylor¹  Albert Serrano¹  Morgan O’Donnell¹  Ken Teter¹  Helen Burress¹  Patrick Cherubin¹  Jessica Guyette¹  Faisal Abedin²  SurenA. Tatulian² 

[1] Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA;Department of Physics, College of Sciences, University of Central Florida, Orlando, FL 32816, USA;

关键词: AB toxin;    cholera toxin;    inhibitor;    polyphenol;    protein disulfide isomerase;    ricin;    rutin hydrate;   

DOI  :  10.3390/toxins11080458

来源: DOAJ

【 摘 要 】

Protein disulfide isomerase (PDI) is mainly located in the endoplasmic reticulum (ER) but is also secreted into the bloodstream where its oxidoreductase activity is involved with thrombus formation. Quercetin-3-rutinoside (Q3R) blocks this activity, but its inhibitory mechanism against PDI is not fully understood. Here, we examined the potential inhibitory effect of Q3R on another process that requires PDI: disassembly of the multimeric cholera toxin (CT). In the ER, PDI physically displaces the reduced CTA1 subunit from its non-covalent assembly in the CT holotoxin. This is followed by CTA1 dislocation from the ER to the cytosol where the toxin interacts with its G protein target for a cytopathic effect. Q3R blocked the conformational change in PDI that accompanies its binding to CTA1, which, in turn, prevented PDI from displacing CTA1 from its holotoxin and generated a toxin-resistant phenotype. Other steps of the CT intoxication process were not affected by Q3R, including PDI binding to CTA1 and CT reduction by PDI. Additional experiments with the B chain of ricin toxin found that Q3R could also disrupt PDI function through the loss of substrate binding. Q3R can thus inhibit PDI function through distinct mechanisms in a substrate-dependent manner.

【 授权许可】

Unknown