Recognition of the polyubiquitin proteolytic signal

Polyubiquitin chains linked through Lys48 are the principal signal for targ eting substrates to the 26S proteasome. Through studies of structurally def ined, polyubiquitylated model substrates, we show that tetra-ubiquitin is t he minimum signal for efficient proteasomal targeting. The mechanism of tar geting involves a simple increase in substrate affinity that is brought abo ut by autonomous binding of the polyubiquitin chain. Assigning the proteaso mal signaling function to a specific polymeric unit explains how a single u biquitin can act as a functionally distinct signal, for example in endocyto sis. The properties of the substrates studied here implicate substrate unfo lding as a kinetically dominant step in the proteolysis of properly folded proteins, and suggest that extraproteasomal chaperones are required for eff icient degradation of certain proteasome substrates.