The Ubiquitin System

Covalent modification of proteins with ubiquitin (ubiquitination) regulates almost all aspects of eukaryotic cellular function. The essential role of the ubiquitin system is evident by its involvement in fundamental cellular processes such as transcriptional and cell cycle regulation, DNA repair, signal transduction, immune response, protein quality control and metabolism.

Three enzymes carry out the covalent attachment of Ubiquitin (Ub) to target proteins: a Ub-activating enzyme, E1; a Ub-conjugating enzyme, E2; and a ubiquitin ligase, E3. The E3 ubiquitin ligase serves two roles: it specifically recognizes ubiquitination substrates and simultaneously recruits an E2.

Ubiquitination of proteins is regulated by the E3 ubiquitin ligases. The human E3 family of proteins consists of hundreds of distinct proteins each of which target a small set of protein substrates for ubiquitination. E3s are divided into distinct classes based on common structural domains and molecular structure: the largest group consists of the single subunit RING-finger containing proteins (variants include the PHD domain and U-box domain). Smaller groups consist of HECT-domain containing E3 ligases and oligomeric RING finger SCF/VCB type E3 ligases.

The essential physiological role of ubiquitination and the high degree of substrate specificity makes E3 ligases attractive therapeutic targets in pathological conditions where the ubiquitin system is involved.