Checking folding inside and out

The ER is a site of both synthesis and quality control. Rejected, improperly folded proteins are destroyed by a well-characterized machinery (the ER-associated degradation [ERAD] pathway) in the cytosol and ER membrane that extracts and chews up any unfolded proteins. But the mechanisms for recognizing unfolded proteins as targets for destruction are less well characterized.

The few unfolded substrates to be examined fall into a simple pattern: transmembrane proteins are recognized by one system and soluble, secreted proteins by another. Vashist and Ng (page 41) take a closer look and find that the two transmembrane proteins previously examined had defects in their cytoplasmic domains. When the defects are instead in the lumenal domains of transmembrane proteins, these proteins are treated in the same way as soluble lumenal proteins.

Thus, the...