Proteasome, Chemistry of

The proteasome is a multisubunit and multifunctional intracellular protease widespread from Archaebacteria to Eukaryota. In the latter, the proteasome is an essential enzyme and a convergence point of the ubiquitin-proteasome pathway (UPP), which provides the major venue for intracellular controlled proteolysis. In the most basic scenario, proteins are tagged by multiple copies of ubiquitin, as such recognized by the proteasome, then deubiquitinated, unfolded, and degraded to short peptides. Following up the evolutionary ladder, the proteasome assemblies gain complexity and diversity. Nevertheless, all of them share the essential catalytic core: a compartmentalized protease exhibiting a common architecture and catalytic mechanism. The core is a tube-shaped particle built from four stacked heptameric rings with active sites concealed inside the two internal rings and self-activated during its assembly. Hydroxyl and amino groups of Thr1 forming a catalytic dyad are employed to break peptide bonds using the N-terminal nucleophile-type mechanism. The proteasomes of higher Eukaryota are equipped with six active sites of specificities imposed by three distinct binding pockets. Binding of additional protein regulators to the core extends its capabilities into new functions, for example, processing of polyubiquitinated substrates. In the serendipitous twist, the proteasome recently became an attractive target for anti-cancer and anti-inflammatory drugs, which propelled studies on the mechanism of actions of the enzyme.