SUMMARY | FULL STORY
Cell Biology
Accomplice Fingered In Cholera Toxicity
The effects of cholera, one of the most rapidly fatal diseases known, are largely due to a toxin secreted by the bacterium
Vibrio cholerae that acts on intestinal epithelial cells. The cholera toxin is a deft invader, making its way backwards through the cell's own pathways for secreting and degrading proteins. Once in the cytosol, the toxin initiates a signaling cascade that results in chloride channels opening at the cellular membrane, causing the massive loss of water and the diarrhea associated with cholera.
The proposed chaperone mechanism of protein disulfide isomerase (PDI) is remarkably similar to known chaperones powered by ATP. In the figure at top, the chaperone Hsp 70 (crescent) binds to and releases a peptide as its binding affinity is changed by ATP hydrolysis. Below, the same action in PDI is governed by the formation and reduction of disulfide bonds. Illustration courtesy of Billy Tsai
A team led by Tom Rapoport, Howard Hughes investigator and HMS professor of cell biology, uncovered part of the toxin's trail in a study published in the March 23
Cell. Much of how cholera toxin carries out its cellular coup has been worked out, but how it is able to get from the lumen of the ER to the cytosol has remained a mystery. Like a prisoner escaping from a locked cell, the toxin slips through the ER membrane even though a protein generally cannot cross a membrane in its folded form. "We assumed that there has to be some enzyme in the ER lumen that can unfold the cholera toxin," said Billy Tsai, HMS research fellow in cell biology and the paper's first author. "Once it unfolds, it can travel across the membrane and get refolded."
Tom Rapoport (left) and Billy Tsai have helped uncover how cholera toxin's path to the cytosol is aided by one of the cell's own enzymes. Photo by Steve Gilbert
The toxin's accomplice seems to be protein disulfide isomerase, or PDI, known for its ability to form and shuffle disulfide bonds. They believe that PDI acts as a new kind of protein chaperone, remarkably similar to known chaperones but driven by disulfide exchanges rather than ATP hydrolysis. PDI's method of disulfide bond swapping can carry out several functions by moving electrons and changing binding properties, similar to ATP-driven mechanisms, and may have broader implications for protein transport within cells.
—Courtney Humphries
Copyright 2001 by the President and Fellows of Harvard College
