Proteasomes are non-lysosomal proteolytic complexes localised primarily in the cytoplasm and in the nucleus of eukaryotic cells. They are responsible for the ubiquitin-mediated degradation of short half-life proteins and peptides that are involved in essential cellular processes including cell-cycle regulation, apoptosis and transcriptional regulation, innate immunity and antigen processing, and in the removal of redundant or damaged proteins. As such protein degradation by the ubiquitin-proteasome pathway has a major regulatory function for proliferation activity and survival of both normal and malignant cells, and its dysfunction has been implicated in a wide range of other disease processes including neurodegenerative, cardiovascular and metabolic disorders.
The 26S proteasome structure is composed of a 20S proteasome catalytic core complex and one or two 19S (PA700) regulatory subcomplexes. The 20S core comprises two copies of 14 subunits (7 alpha subunits and 7 beta subunits) arranged in a a7B7B7a7 cylindrical array. Proteolytic activities are determined by the B1 (caspase-like), B2 (trypsin-like) and B5 (chymotrypsin-like) subunits, access to which is guarded by the a-subunits. The 19S regulatory unit consists of six ATPase and at least ten non-ATPase subunits that are required for ubiquitinated protein binding, deubiquitination, substrate unfolding and translocation to the 20S catalytic core.
Varying catalytic subunit composition (B1, B1i; B2, B2i; B5, B5i) results in a variety of possible subtypes from full constitutive proteasome (B1, B2, B5) through mixed populations to full inducible / immunoproteasome (B1i, B2i, B5i). Alternative regulatory complexes such as the PA200 and 11S proteasome activators confer different substrate specificities and activity compared to the 19S regulator.
