26S Proteasome: Structure and Function

The 26S proteasome is a molecular machine of approximately 2.5 MDa, which degrades ubiquitylated proteins in an ATP dependent manner. It comprises two modules, the core particle (CP) and one or two copies of asymmetric 19S regulatory particles (RPs), which bind to the end(s) of the barrel-shaped CP. Proteolytic action occurs at the heart of the CP, whereas the 19S RP is responsible for regulation of CP, which involves substrate recognition, substrate deubiquitylation, opening of the gate to the inner cavity of the CP, substrate unfolding, and translocation to the CP.

Here, we describe the assembly, structure, mechanism, and function of the 26S proteasome based on recent structural and molecular studies. Cryoelectron microscopy maps of the 26S proteasome and crystal structures have unveiled the molecular architecture of the 26S proteasome. Conformational switching modulates proteasomal substrate degradation and its deubiquitylation in an ATP-dependent manner. An increasingly complex picture of proteasomal regulation in the cell emerges: while the RP regulates activity of the CP, many proteasome-interacting proteins (PIPs) in turn modulate RP function. Thus, a complex molecular machinery enables spatially and temporally regulated proteasomal degradation.