Proteasomes

Proteasomes are large proteolytic protein complexes responsible for the regulated degradation of intracellular proteins. In eukaryotes and many archaea, the main form is the 26S proteasome, consisting of a central 20S core particle capped at one or two ends by regulatory particles known as the 19S caps. The 20S core is a hollow cylinder formed by four stacked seven-membered rings (alpha1–7, beta1–7, beta1–7, alpha1–7). The inner beta rings contain the proteolytic active sites, with catalytic subunits β1, β2, and β5 performing caspase-like, trypsin-like, and chymotrypsin-like proteolysis, respectively. The active sites utilize an N-terminal threonine as the nucleophile.

The 19S regulatory particle recognizes polyubiquitin chains on substrate proteins, removes the ubiquitin tags, unfolds the substrates, uses ATP to power their unfolding, and threads them into the 20S core for degradation. A proteasome can bind one or two 19S caps to form the 26S proteasome; alternative regulators such as PA28 (11S) or PA200 can also associate with the core to modulate activity.

Substrates are typically tagged with polyubiquitin chains, especially K48-linked chains, signaling their delivery to the proteasome. Beyond protein quality control, proteasomes regulate many cellular processes, including cell cycle progression, DNA repair, and signaling. In immune cells, immunoproteasomes containing alternative catalytic subunits β1i, β2i, and β5i enhance generation of peptides for MHC class I antigen presentation.

Clinically, proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib are used to treat certain cancers, notably multiple myeloma. Dysfunctions of proteasomes are associated with neurodegenerative diseases and aging, making them a focus of biomedical research.