The Role of the Selective Adaptor p62 and Ubiquitin-Like Proteins in Autophagy

Figure 2

The ubiquitin-proteasome system. An enzyme cascade organizes the attachment of mono- or polyubiquitin to the substrates. Ubiquitin (Ub) is first activated in an ATP-consuming reaction by E1 (Ub-activating enzyme), to which it becomes attached by a high-energy thiolester bond. Then, the activated Ub is shifted to the active Cys residue of E2 (ubiquitin-conjugating enzyme). E2 catalyzes the transfer of ubiquitin to the substrate protein with the help of E3 (ubiquitin ligase). There are two major classes of E3 enzymes, characterized by the HECT domain or the RING-finger domain. In case of the HECT E3 enzymes, the activated Ub is transferred first to an active Cys residue in the HECT domain before it is finally moved to the substrate. RING-finger domain E3 enzymes bind to both the E2 enzyme and the substrate and catalyze the transfer of Ub directly from the E2 enzyme to the substrate. A polyubiquitin chain linked through Lys 48 is the signal for the proteasome to degrade the substrate. The 26S proteasome consists of the catalytic 20S core particle; a barrel of four stacked rings: two outer α-rings (blue) and two inner β-rings (red); and the 19S regulatory particle. The polyubiquitin chain is recognized by the regulatory particle, which then binds, unfolds, and translocates the polypeptide into the catalytic core. The substrate is hydrolyzed by the enzymatically active β-subunits inside the core particle producing short peptides. Ubiquitin is recycled in the process [102, 103].