Ubiquitin - Ubiquitin Chains

The type and number of poly-ubiquitin chains that are conjugated to a target is highly regulated to generate distinct signals that affect different physiological processes. This versatility arises from the fact that not only can targets be mono-ubiquitinated or poly-ubiquitinated, but also that different types of poly-ubiquitin chains are formed. Proteins tagged with ubiquitin are most often destined for degradation by the proteasome. However, mono-ubiquitination and poly-ubiquitination also has non-proteasomal regulatory functions like targeting proteins to nucleus, cytoskeleton and endocytic machinery, or modulating enzymatic activity and protein-protein interactions. Multi-ubiquitin chains are built by formation of an isopeptide bond between Gly76 of one ubiquitin to the ε-NH2 group of one of the seven potential lysines (K6, K11, K27, K29, K33, K48 or K63) of the preceding ubiquitin. Specific E2 enzymes and E2/E3 combinations result in the formation of linkage-specific ubiquitin chains. Residue K48 is a major site of chain initiation and K48-linkages are highly abundant, being the predominant signal for proteins destined for degradation by the proteasome. The other principle and relatively abundant poly-ubiquitin chain has K63-linkages. K63-linkages do not seem to play a role in protein turnover and have been implicated in receptor endocytosis and sorting, translation, DNA damage repair, the stress response and signaling.