Proteasome 20S core subunit beta type-5 (chymotrypsin-like site of the 26S proteasome) (PSMB5 (β5))

The 26S proteasome is a ~2.5 MDa ATP-dependent protease comprising a 20S core particle capped by one or two 19S regulatory particles; it degrades polyubiquitylated proteins in the cytosol and nucleus. The 20S core has four stacked heptameric rings (α7–β7–β7–α7); proteolytic active sites are in the β rings, with three principal activities: trypsin-like (β2), chymotrypsin-like (β5), and caspase-like (β1). The β5 subunit provides the chymotrypsin-like activity via an N-terminal threonine catalytic mechanism exposed after propeptide removal during maturation. The 19S cap recognizes polyubiquitin, deubiquitylates, unfolds, and translocates substrates into the 20S core for degradation, thereby regulating many cellular processes including the cell cycle, DNA replication, transcription, signaling, and stress responses. Clinically, the β5 chymotrypsin-like site is the primary target of approved proteasome inhibitors used in multiple myeloma and related malignancies.

Other names

Proteasome chymotrypsin-like siteβ5 subunit; beta 5 subunitPSMB5Proteasome subunit beta type-5CT-L activity; chymotryptic activity

Reversible boronate inhibition of the β5 threonine protease active site (e.g., bortezomib), blocking chymotrypsin-like proteolysis and causing accumulation of ubiquitylated proteins, leading to apoptosis in rapidly dividing cells. Irreversible epoxyketone inhibition of β5 (e.g., carfilzomib), covalently modifying the N-terminal threonine and more selectively shutting down chymotrypsin-like activity.