ATP-dependent proteases degrade their substrates by processively unraveling them from the degradation signal

Protein unfolding is a key step in several cellular processes, including pr otein translocation across some membranes and protein degradation by ATP-de pendent proteases. ClpAP protease and the proteasome can actively unfold pr oteins in a process that hydrolyzes ATP. Here we show that these proteases seem to catalyze unfolding by processively unraveling their substrates from the attachment point of the degradation signal. As a consequence, the abil ity of a protein to be degraded depends on its structure as well as its sta bility. In multidomain proteins, independently stable domains are unfolded sequentially. We show that these results can explain the limited degradatio n by the proteasome that occurs in the processing of the precursor of the t ranscription factor NF-kappaB.