K63linkitetyt

K63linkitetyt, or K63-linked polyubiquitin chains, are chains of ubiquitin molecules connected through the lysine-63 residue of adjacent ubiquitin units. These linkages are distinct from the Lysine-48–linked chains, which predominantly target proteins for proteasomal degradation; K63-linked chains mainly regulate signaling and other non-degradative processes.

Formation and enzymes: Ubiquitin activation begins with an E1 enzyme, with transfer to an E2 conjugating enzyme. For K63 chains, a key E2 pair is UBE2N (UBC13) in combination with a cofactor such as UBE2V2/MMS2. E3 ligases, including RNF8, RNF168, and TRAF6, catalyze chain assembly on substrates, shaping signaling outcomes rather than directing degradation.

Functions: K63-linked ubiquitination participates in DNA damage signaling, innate immune pathways, and membrane trafficking. It helps recruit DNA repair factors to damage sites, modulates NF-κB signaling, promotes endocytosis, and can influence autophagy. The chains act as scaffolds that recruit proteins with specific ubiquitin-binding domains, influencing the assembly of signaling complexes.

Regulation: Deubiquitinases such as CYLD and AMSH can remove K63 chains, providing a counterbalance to signaling and ensuring timely termination of responses. The balance between formation and removal of K63 linkages helps control cellular signaling networks.

Significance and detection: Abnormal K63 ubiquitination is associated with cancer, inflammatory diseases, and neurodegeneration, making it a focus of biomedical research. Researchers detect K63 linkages using linkage-specific antibodies and mass spectrometry, enabling study of their dynamics in cells and tissues.