Proteasome

Proteasomes are large protein complexes that carry out controlled proteolysis in cells. They are the central component of the ubiquitin-proteasome system (UPS), which marks unwanted or damaged proteins with ubiquitin and directs them to degradation. Proteasomes regulate many cellular processes by removing regulatory proteins and by generating peptide fragments for immune surveillance.

The most common form in eukaryotes is the 26S proteasome, consisting of a 20S core particle capped by one or two 19S regulatory particles. The 20S core is a cylindrical proteolytic chamber built from four stacked rings of seven subunits (α7β7β7α7). The inner chamber contains catalytic β subunits with three protease activities: β1 (caspase-like), β2 (trypsin-like), and β5 (chymotrypsin-like). The 19S regulatory particle recognizes polyubiquitin chains, unfolds substrates, and translocates them into the core; it also contains deubiquitinating enzymes that recycle ubiquitin and ATPases that provide energy for unfolding and translocation.

In immune cells, alternative proteasome forms called immunoproteasomes incorporate different catalytic subunits (β1i, β2i, β5i) and can alter peptide generation for antigen presentation by MHC class I. Activity can also be modulated by 11S regulators (PA28) or by PA200.

Proteasome dysfunction or inhibition has medical relevance. Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib are used in cancer therapy, particularly multiple myeloma, by disrupting degradation and inducing cancer cell death. The UPS is also implicated in neurodegenerative diseases and aging, where impaired proteostasis contributes to pathogenesis.