26S

The 26S proteasome is a large proteolytic complex in eukaryotic cells that degrades ubiquitin-tagged proteins in an ATP-dependent manner. It physiologically maintains protein homeostasis, regulates many cellular processes by removing short-lived regulatory proteins, and contributes to antigen presentation through peptide generation for MHC class I.

Structure and composition: The 26S proteasome consists of a 20S core particle (CP) capped by one or two 19S regulatory particles. The 20S CP is a cylindrical proteolytic chamber formed from four stacked rings (two outer alpha rings and two inner beta rings). The catalytic activity resides in the beta subunits, with distinct proteolytic specificities (β1, β2, β5). The 19S regulatory particle recognizes ubiquitinated substrates, unfolds them using ATPase subunits (Rpt1–Rpt6) in its base, and cleaves off attached ubiquitin chains via deubiquitinating enzymes. The lid contains non-ATPase subunits that aid substrate processing and recognition.

Function and mechanism: Substrates tagged with polyubiquitin are recognized by receptors such as Rpn10 and Rpn13 on the 19S cap. Ubiquitin chains are removed or trimmed by DUBs (including Rpn11) as the substrate is unfolded and threaded into the 20S core. ATP hydrolysis by the 19S base drives unfolding and translocation through the central gate of the CP, where proteolysis occurs. Resulting peptide fragments are released into the cytosol or imported into the nucleus.

Regulation and variants: Proteasome activity is modulated by cellular signals and can be inhibited pharmacologically (notably by proteasome inhibitors such as bortezomib and carfilzomib, used in cancer therapy). A related form, the immunoproteasome, substitutes alternative catalytic subunits (for example LMP2, LMP7, MECL-1) in response to immune signaling, enhancing generation of antigenic peptides.