proteasomale

Proteasomale, often referred to as proteasomes, are large protease complexes responsible for ATP-dependent degradation of ubiquitin-tagged proteins in eukaryotic cells. They form part of the ubiquitin–proteasome system (UPS), which maintains protein quality and regulates many cellular processes through controlled protein turnover. The core particle, the 20S proteasome, consists of four stacked rings of seven subunits, creating an internal proteolytic chamber. Regulatory particles, such as the 19S cap, recognize ubiquitinated substrates, unfold them, and feed them into the core.

The ubiquitin-tagged substrates bind to the 19S regulatory particle, which uses ATP to unfold substrates and remove ubiquitin chains. The substrates are translocated into the 20S core, where proteolysis occurs. The core contains catalytic sites with chymotrypsin-like, trypsin-like, and caspase-like activities. In addition to the 26S proteasome, alternative activators such as PA28/11S or PA200 can bind the 20S core and promote proteolysis in ubiquitin-independent pathways.

Role in biology: Proteasomes regulate cell cycle progression, signal transduction, and stress responses. They generate peptides for MHC class I antigen presentation, contributing to adaptive immunity. Dysfunction of proteasome activity is associated with cancers, various neurodegenerative diseases, and aging. Inhibiting proteasomes selectively can disrupt malignant cells while sparing normal cells, illustrating its importance in medicine.

Clinical relevance: Proteasome inhibitors such as bortezomib (Velcade), carfilzomib, and ixazomib have demonstrated efficacy in multiple myeloma and certain lymphomas by perturbing protein homeostasis and triggering apoptosis. Side effects and resistance are ongoing challenges, spurring research into more selective inhibitors, combination therapies, and a deeper understanding of immunoproteasome function and non-proteolytic proteasome roles.