3. Degradation of cellular proteins via proteasomal system

An important feature of many of the neurodegenerative diseases is the apparent breakdown in the ability of the cell to rid itself of proteins which have been designated for degradation via the proteosomal system. In normal circumstances cellular proteins are degraded via the ATP-dependent ubiquitin system which also involves the 26S proteasome (Figure 3). Proteins that have been marked out for degradation are identified by covalent coupling to ubiquitin, a 76 residue protein which is both ubiquitous and abundant in eukaryotes. The attachment of the ubiquitin tag to the condemned protein involves three steps.. In the first step, ubiquitin is bound by its carboxyl terminus to ubiquitin-activating enzyme, E₁ in an ATP-dependent process. Most organisms, including humans, have only one E₁. Ubiquitin is then transferred to the thiol group of one of a number of ubiquitin-conjugating enzymes, E₂s, of which there are over 20 in mammals. Then, the ubiquitin-protein ligase (E₃) transfers the ubiquitin from E₂ to the amino group of a Lys residue of its target protein, forming an isopeptide bond. Ubiquinated proteins are subsequently proteolytically degraded by the large (2000kD) multisubunit protein complex, the 26S proteasome. In this process, the ubiquitin molecules themselves are not degraded, but are returned to the cell for reutilisation.