ubiquitination

Ubiquitination is a post-translational modification process in which the small ubiquitin-like modifier protein ubiquitin is covalently attached to a target substrate, typically a protein. This modification plays a central role in regulating various cellular processes, including protein degradation, signal transduction, DNA repair, and cell cycle progression. The process involves a three-enzyme system: an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase.

Ubiquitin is synthesized as a precursor protein that is cleaved to remove a methionine residue, yielding the mature 76-amino-acid ubiquitin molecule. The E1 enzyme activates ubiquitin by forming a thioester bond with its C-terminal glycine residue. This activated ubiquitin is then transferred to an E2 enzyme, which functions as a ubiquitin carrier protein. The E3 ligase facilitates the transfer of ubiquitin from the E2 to the substrate protein, typically at lysine residues, though other amino acids can also serve as targets.

Ubiquitination can be reversible, mediated by deubiquitinating enzymes (DUBs) that remove ubiquitin from substrates. The extent and pattern of ubiquitination determine the fate of the target protein. Monoubiquitination, polyubiquitination (with multiple ubiquitin molecules attached), or other ubiquitin modifications like K63-linked or linear ubiquitination can influence different cellular outcomes. For example, polyubiquitination often signals for proteasomal degradation, while monoubiquitination can regulate nuclear transport or DNA repair.

Ubiquitination is essential for maintaining cellular homeostasis and is dysregulated in various diseases, including cancer, neurodegenerative disorders, and autoimmune conditions. Understanding the intricacies of ubiquitination provides insights into potential therapeutic targets for these conditions.