Ubiquitin ligases are part of a crucial regulatory mechanism dedicated to degrade and remove misfolded and denatured proteins by linking a chain of ubiquitin peptides to the targeted protein. The process involves Enzyme 1 (E1) that activates ubiquitin by forming a thioester bond, an ubiquitin conjugation enzyme (E2) that binds to the activated ubiquitin, and an ubiquitin ligase (E3) to link the ubiquitin to the targeted protein. This process goes through several cycles where the next ubiquitin is linked to the former until the polyubiquinated protein is recognized by the proteosome. A particular cell usually contains only a few types of E1 molecule, a greater diversity of E2s, and a very large variety of E3s.
In general, polyubiquitination leads to protein degradation in proteasomes, while monoubiquitination is a signal for protein endocytosis leading to lysosomal degradation.
Polyubiquination usually involves Lys48 in the ubiquitin peptide. This ubiquitinated lysine is recognized by the proteasome. However, Lys63 can also be used, and chains using this lysine are important for DNA repair, amongst other functions.
Mutations in ubiquitin ligases can cause genetic disorders, such as Fanconi anemia, Angelman-, Von Hippel-Lindau-, Liddle’s and 3-M syndrome.

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