Ubiquitinated

Ubiquitination is the covalent attachment of ubiquitin, a small regulatory protein, to substrate proteins. This reversible post-translational modification regulates a wide range of cellular processes. Ubiquitination is carried out by a cascade of enzymes: an E1 ubiquitin-activating enzyme activates ubiquitin, an E2 ubiquitin-conjugating enzyme transfers it, and an E3 ubiquitin ligase confers substrate specificity by binding both ubiquitin and the target protein.

Ubiquitin can be attached as a single molecule (mono-ubiquitination) or as polyubiquitin chains. Chains are formed when the C-terminus of one ubiquitin is linked to a lysine residue on another ubiquitin, generating chains with different linkage types and functions. The best characterized are K48-linked chains, which often signal for proteasomal degradation, and K63-linked chains, which participate in signaling, DNA repair, and endocytosis. Other linkages and linear head-to-tail chains expand the range of outcomes associated with ubiquitination.

Consequences of ubiquitination include targeted degradation by the 26S proteasome, altered protein activity or interactions, and changes in cellular localization. The specific outcome depends on the linkage type, chain length, and the cellular context, as well as the involvement of auxiliary factors such as cofactors and scaffold proteins.

Regulation of ubiquitination is dynamic and achieved in part by deubiquitinating enzymes (DUBs) that remove ubiquitin, reversing the signal. Dysregulation of ubiquitination pathways is linked to various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions.

Experimental study of ubiquitination relies on methods such as mass spectrometry to identify ubiquitination sites and diGly remnants, biochemical assays, and ubiquitin-specific antibodies.