The 26 S proteasome: from basic mechanisms to drug targeting

Abstract

The regulated degradation of proteins within eukaryotes and bacterial cells is catalyzed primarily by large multimeric proteases in ATP-dependent manner. In eukaryotes, the 26 S proteasome is essential for the rapid destruction of key regulatory proteins, such as cell cycle regulators and transcription factors, whose fast and tuned elimination is necessary for the proper control of the fundamental cell processes they regulate. In addition, the 26 S proteasome is responsible for cell quality control by eliminating defective proteins from the cytosol and endoplasmic reticulum. These defective proteins can be misfolded proteins, nascent prematurely terminated polypeptides, or proteins that fail to assemble into complexes. These diverse activities and its central role in apoptosis have made the proteasome an important target for drug development, in particular to combat malignancies.

FIGURE 1.

A, ribbon representation of the three-dimensional structure of ubiquitin (Protein Data Bank code 1UBI). The seven lysine residues and the C-terminal glycine are depicted as balls and sticks. Note that six of the lysine residues (positions 6, 11, 27, 29, 33, and 48) are located around the midplane of the structure, whereas Lys⁶³ and the C-terminal glycine define the long axis of the molecule. B, the 26 S proteasome. Left, two-dimensional model of the 26 S proteasome generated through averaging of electron micrographs. Right, schematic representation of the 26 S proteasome. The 26 S proteasome is composed of one 20 S complex (lower), which is made of four seven-membered rings. The active sites reside on the β-rings in the center of the structure (β1, β2, and β5). The 26 S proteasome contains one or two 19 S regulatory particles. The regulatory particle can be further subdivided into the lid and the base. The subunit organization of the 19 S particle was adapted from Ref. . RP, regulatory particle; CP, core particle.