Proteasome degradation: enter the substrate

Cells depend upon the regulated destruction of their various proteins to maintain homeostasis and change their metabolic state. A key component of this process is the proteasome - a large multisubunit protease whose catalytic sites are sequestered within a central chamber. Entry of substrates into proteasomes is regulated by activators and is generally thought to proceed sequentially, starting from one end of the substrate polypeptide. This conventional view is expanded by a recent paper, which indicates that some unfolded substrates can open the entrance to the proteolytic chamber in the absence of an activator and can enter the proteasome in a hairpin conformation to allow limited proteolysis of internal segments.