ubiquitinations

Ubiquitinations refer to the biochemical modification of target proteins through the covalent attachment of ubiquitin, a small regulatory protein. This post‑translational modification is catalyzed by a cascade of enzymes: E1 ubiquitin‑activating enzymes, E2 ubiquitin‑conjugating enzymes, and E3 ubiquitin‑ligases, which confer substrate specificity. The ubiquitin molecule has seven lysine residues and an N‑terminus that can form isopeptide bonds with the side chain of lysine residues on substrate proteins or with the N‑terminus of the substrate itself. A single ubiquitin moiety added is called monoubiquitination; chains of ubiquitin linked through different lysine residues generate polyubiquitin chains that signal distinct cellular outcomes. Most commonly, K48‑linked polyubiquitin tags proteins for degradation by the 26S proteasome, a key mechanism of protein quality control. However, other linkage types such as K63, K27, and K11 can mediate signaling, DNA repair, endocytosis, and other non‑proteolytic pathways.

Ubiquitinations are essential for many cellular processes, including cell cycle control, signal transduction, DNA damage response, and innate immunity. Dysregulation of ubiquitination is implicated in numerous diseases, notably neurodegenerative disorders like Parkinson's and ALS, cancers, and immune‑related conditions. Therapeutic strategies targeting ubiquitination machinery are an active area of research, with proteasome inhibitors such as bortezomib already approved for multiple myeloma. Recent advances also focus on proteolysis‑targeting chimeric molecules (PROTACs) that harness the ubiquitin system to degrade specific disease‑associated proteins.