Ubiquitin

Ubiquitin is a small regulatory protein found in all eukaryotes. It comprises 76 amino acids and weighs about 8.5 kDa. Ubiquitin is highly conserved and can be covalently attached to substrate proteins to influence their fate. Attachment can be mono-, multi-, or polyubiquitination; polyubiquitin chains are linked through one of ubiquitin’s seven lysine residues, most commonly K48 and K63, and different linkages elicit distinct outcomes.

Ubiquitination occurs through a cascade of enzymes: an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase that provides substrate specificity. The ubiquitin is attached to substrates via an isopeptide bond between the C-terminal glycine of ubiquitin and a lysine on the target protein. Deubiquitinating enzymes (DUBs) can remove ubiquitin and edit chains, recycling ubiquitin for further use.

Functionally, ubiquitin regulates protein turnover by targeting substrates for degradation by the 26S proteasome, and it participates in many cellular processes, including cell cycle control, DNA repair, transcription, endocytosis, and signaling. Dysregulation of ubiquitination is linked to cancer, neurodegenerative diseases, and immune disorders, and components of the ubiquitin–proteasome system are targets for therapeutics such as proteasome inhibitors.

Discovery of the ubiquitin–proteasome system came to light in the 1980s, with key contributions from researchers including Aaron Ciechanover, Avram Hershko, and Irwin Rose, who were awarded the Nobel Prize in Chemistry in 2004 for this work. Ubiquitin is encoded by several genes in humans and can be produced as fusion proteins that are processed to mature ubiquitin.