Protein degradation through the ubiquitin (Ub)-proteasome pathway. Most proteins that are destined for degradation through the Ub-proteasome pathway are first subjected to polyubiquitination. This is accomplished in several stages. (a) The E1 Ub-activating enzyme, in an ATP-dependent reaction, forms an activated complex with Ub and transfers it to the E2 Ub-conjugating protein. (b) The E2 Ub-conjugating protein then transfers Ub to an E3 Ub-ligase protein, which has formed a complex with the target protein. In some cases an E3 Ub-ligase may not be necessary. (c) After several cycles of ubiquitination, the polyubiquitinated target protein is recognized by the proteasomal cap proteins (shaded gray and labeled 19 S cap) through its ubiquitin moieties, which are cleaved off by isopeptidases and recycled. (d) In an ATP-dependent fashion the protein is then unwound and fed into the 20S core through an interior channel, where it is exposed to the active proteolytic enzymes (shaded black). (e) Oligopeptide digestion products (OP) are then released and degraded further to amino acids by oligopeptidases. Some proteins may be subject to proteasomal degradation without the need for prior ubiquitination. Please note that this schematic diagram does not represent the various components to scale. Interested readers are referred to several excellent recent reviews with more detailed descriptions of this pathway [43, 44].