A protein’s fate in a cell’s garbage disposal system rests in part on the stability of the protein’s folded regions, Northwestern University researchers report (ACS Chem. Biol., DOI: 10.1021/cb2002285). The proteasome regulates protein turnover and requires two things to commence protein destruction: a tag made from multiple copies of the protein ubiquitin and an unfolded region near the tag for the proteasome to start degradation. But it had been unclear whether placement of that initiation point could affect the distribution of degradation products. Northwestern’s Daniel A. Kraut and Andreas Matouschek built model proteasome substrates to test the effects of various initiation points. They found that stably folded protein domains flanking an initiation site can protect each other from degradation without interacting directly. This setup can lead to release of partially degraded proteins with new bioactivities, instead of small peptides, which are the normal end points of degradation. Michael Glickman, who studies the biochemistry of protein degradation at Technion-Israel Institute of Technology, praises the work. Glickman notes that a few published cases of partial protein degradation exist, and that the phenomenon could be more common than researchers currently appreciate.