Proteasome

Selective destruction of individual proteins is carried out by the ubiquitin–proteasome system. Ubiquitin, a 76-amino-acid protein, is attached to lysine residues of target proteins by an enzyme cascade: E1 (activating, uses ATP), E2 (conjugating) and E3 (ligase, of which there are hundreds, conferring substrate specificity). A chain of ≥4 ubiquitins linked through lysine-48 marks the protein for degradation.

The 26S proteasome (≈2.5 MDa) consists of a 20S core particle — a hollow cylinder of four stacked seven-membered rings (α7β7β7α7) whose inner β-subunits have caspase-like, trypsin-like and chymotrypsin-like activity — capped at one or both ends by a 19S regulatory particle. The cap recognises polyubiquitin, removes and recycles the ubiquitin, and uses ATPases to unfold the substrate and thread it into the core, where it is cut into short peptides (≈3–25 amino acids).

Substrates include misfolded proteins (including those retro-translocated from the ER by ERAD) and short-lived regulators such as cyclins, securin, p53 (via the E3 MDM2), IκB (allowing NF-κB activation) and β-catenin. Peptides produced by immunoproteasomes (induced by interferon-γ) are loaded onto MHC class I molecules for presentation to cytotoxic T cells.