title: Substrate-induced unfolding of protein disulfide isomerase displaces the cholera toxin A1 subunit from its holotoxin.
abstract: To generate a cytopathic effect, the catalytic A1 subunit of cholera toxin (CT) must be separated from the rest of the toxin. Protein disulfide isomerase (PDI) is thought to mediate CT disassembly by acting as a redox-driven chaperone that actively unfolds the CTA1 subunit. Here, we show that PDI itself unfolds upon contact with CTA1. The substrate-induced unfolding of PDI provides a novel molecular mechanism for holotoxin disassembly: we postulate the expanded hydrodynamic radius of unfolded PDI acts as a wedge to dislodge reduced CTA1 from its holotoxin. The oxidoreductase activity of PDI was not required for CT disassembly, but CTA1 displacement did not occur when PDI was locked in a folded conformation or when its substrate-induced unfolding was blocked due to the loss of chaperone function. Two other oxidoreductases (ERp57 and ERp72) did not unfold in the presence of CTA1 and did not displace reduced CTA1 from its holotoxin. Our data establish a new functional property of PDI that may be linked to its role as a chaperone that prevents protein aggregation.
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.
authors: Michael
authors: M
authors: Taylor
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.
authors: Helen
authors: H
authors: Burress
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.
authors: Tuhina
authors: T
authors: Banerjee
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.
authors: Supriyo
authors: S
authors: Ray
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.
authors: David
authors: D
authors: Curtis
authors: Department of Physics, University of Central Florida, Orlando, Florida, United States of America.
authors: Suren A
authors: SA
authors: Tatulian
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.
authors: Ken
authors: K
authors: Teter
mesh_terms: D000818:Animals; D016466:CHO Cells; D002772:Cholera Toxin / Q000737:chemistry* / Q000378:metabolism*; D003412:Cricetulus; D019704:Protein Disulfide-Isomerases / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding
chemical_list: D002772:Cholera Toxin; D019704:Protein Disulfide-Isomerases