The ability of the proteasome to recognize both a Ub chain and a loosely folded region provides the fundamental basis for how it determines which proteins to degrade and which to spare. This critical life-or-death decision can be explained by the discovery of two types of conjugate binding: 1) an initial, reversible step in which the Ub chain undergoes high affinity binding to receptors on the 26S particle, and 2) a subsequent tighter-binding step that depends on the ubiquitylated protein's structure and requires ATP hydrolysis (). This sequence and the “dwell-time” of the substrate on the 26S provide an opportunity for competing processes to determine the protein's fate. On one hand, the proteasome's multiple de-ubiquitylation enzymes (DUBs) () shorten the substrate's dwell-time and promote the release of some, perhaps many, of the ubiquitylated proteins that initially bind (). However, if the substrate becomes tightly bound through its loosely folded domain, the six proteasome ATPases are activated (), and the substrate becomes committed to the steps leading to its destruction —further deubiquitylation, unfolding, processive translocation, and hydrolysis to small peptides in the 20S core particle.