26S proteasome 20S core subunit beta 1 and beta 2 (PSMB6 and PSMB7)

The 26S proteasome is a massive multi-subunit protease complex essential for maintaining cellular protein homeostasis by degrading misfolded or short-lived proteins tagged with ubiquitin (UniProt P28072, Q99436). The 20S core particle serves as the catalytic engine of this complex, containing three pairs of active sites: the beta 1 (PSMB6) subunit providing caspase-like activity, the beta 2 (PSMB7) subunit providing trypsin-like activity, and the beta 5 subunit providing chymotrypsin-like activity (PubMed: 26151217). These subunits utilize a unique N-terminal threonine residue to perform peptide bond hydrolysis. In hematological malignancies like multiple myeloma, cells are highly dependent on proteasome activity to manage the high volume of immunoglobulin production; thus, inhibiting these subunits leads to the accumulation of toxic protein aggregates, endoplasmic reticulum stress, and programmed cell death (StatPearls: NBK542311). While many clinical proteasome inhibitors primarily target the beta 5 subunit, secondary inhibition of the beta 1 and beta 2 subunits is often required to achieve maximal therapeutic efficacy and overcome drug resistance (PubMed: 21112705).

Other names

Proteasome subunit beta type-6Proteasome subunit beta type-720S proteasome subunit beta-120S proteasome subunit beta-2PSMB6PSMB7Macropain subunit deltaMacropain subunit Z

Inhibition of the catalytic N-terminal threonine residue within the beta subunits of the 20S core, preventing the degradation of polyubiquitinated proteins and inducing proteotoxic stress and apoptosis.