Ubiquitinates

Ubiquitinates is the action of attaching ubiquitin to a substrate protein, a regulatory modification that affects protein fate and function. Ubiquitin is a small, highly conserved protein of 76 amino acids; its covalent attachment typically occurs on lysine residues, though monoubiquitination can occur on other sites as well.

The process is carried out by a cascade of enzymes: E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. E1 activates ubiquitin in an ATP-dependent step and passes it to E2; E3 ligases recognize the substrate and catalyze the transfer of ubiquitin from the E2 to the target. This cascade can attach a single ubiquitin (monoubiquitination) or form polyubiquitin chains, depending on the context and the enzymes involved. E3 ligases determine substrate specificity, making ubiquitination highly regulated and diverse.

Ubiquitin chains convey different cellular outcomes. Lysine-48–linked polyubiquitin typically marks proteins for degradation by the 26S proteasome. Other linkages, such as Lys-63– and Lys-11–linked chains, participate in signaling, DNA repair, endocytosis, and autophagy. Monoubiquitination can modulate protein activity, interactions, localization, or trafficking without prompting degradation. The ubiquitin–proteasome system (UPS) is a central pathway for controlled protein turnover, but ubiquitination also regulates many processes independently of degradation.

Dysregulation of ubiquitination pathways is implicated in diseases including cancer, neurodegenerative disorders, and immune dysfunction. Because of its central role in cellular regulation, components of the ubiquitination machinery are targets of therapeutic research, aiming to modulate protein stability and signaling pathways.