Cholera toxin travels from the plasma membrane to the endoplasmic reticulum of host cells,
where a portion of the toxin, the A1-chain, is unfolded and targeted to a protein-conducting
channel for retrotranslocation to the cytosol. Unlike most retrotranslocation substrates, the
A1-chain escapes degradation by the proteasome and refolds in the cytosol to induce
disease. How this occurs remains poorly understood. Here, we show that an unstructured
peptide appended to the N terminus of the A1-chain renders the toxin functionally inactive …