Proteasomi

Proteasomes (proteasomi in Italian) are large proteolytic complexes that degrade intracellular proteins marked for destruction. They are central components of the ubiquitin-proteasome system (UPS), which tags substrates with ubiquitin and funnels them to the proteasome for degradation.

The core particle, the 20S proteasome, is a cylindrical structure formed by four stacked rings: two outer alpha rings and two inner beta rings. The inner chamber contains the proteolytic active sites. In many cells, the 20S core associates with one or more 19S regulatory particles to form the 26S proteasome. The 19S cap recognizes polyubiquitinated substrates, unfolds them, and translocates them into the core in an ATP-dependent process. Alternative regulatory caps such as PA28 (11S) or PA200 can cap the 20S core, modulating peptide production.

Catalytic activity is provided primarily by the beta1, beta2, and beta5 subunits, delivering caspase-like, trypsin-like, and chymotrypsin-like proteolysis, respectively. Proteasomes regulate numerous cellular processes by removing short-lived regulatory proteins and misfolded proteins, and they generate peptides for MHC class I antigen presentation.

Immunoproteasomes form in response to inflammatory cytokines and replace certain catalytic subunits (beta1i, beta2i, beta5i), altering peptide output for immune surveillance. Dysfunction or inhibition of proteasomes is associated with neurodegenerative diseases and cancer; proteasome inhibitors such as bortezomib and carfilzomib are used clinically to treat multiple myeloma and other malignancies.