Abstract

1.1. The ubiquitin-proteasome pathway Ubiquitin is a highly conserved, 76-amino acid protein that is ubiquitously expressed in eukaryotic cells 1. This small protein controls almost all aspects of a cell's life and death, through its covalent modification of other cellular proteins in a process known as ubiquitination 2,3. The enzymatic cascade of ubiquitination begins with ubiquitin activation by an E1 (ubiquitin-activating enzyme), followed by transfer of the activated ubiquitin to an E2 (ubiquitin-conjugating enzyme, also known as Ubc), and ends with conjugation of ubiquitin to a target protein through the formation of an isopeptide bond between the carboxyl terminus of ubiquitin and an e-amino group of a lysine residue on the protein substrate. The last step requires a member of a very large family of ubiquitin-protein ligases (E3), which, together with E2s, determine substrate specificity. E3s can be divided into two categories, depending on whether they contain a HECT (homology to E6AP C-terminus) or RING (really interesting new gene) domain. The HECT domain E3s contain an active-site cysteine, which can accept ubiquitin from an E2 and transfer the ubiquitin to a target protein. In contrast, the RING domain E3s do not contain a conventional enzyme active site, but they promote ubiquitination by binding to both protein substrates and E2s, facilitating the conjugation of ubiquitin to specific protein targets. Ubiquitination reactions are reversed by members of a large family of deubiquitination enzymes (DUBs, also known as isopeptidases)4,5. Thus, ubiquitination is a reversible covalent modification, similar to phosphorylation. Ubiquitin has seven lysines, each of which can be conjugated by another ubiquitin to form a polyubiquitin chain 6. The topology of polyubiquitin chains can influence the fate of target proteins. For example, polyubiquitin chains linked through lysine 48 (K48) of ubiquitin normally target a protein for degradation by the proteasome, whereas K63 polyubiquitin chains have functions independent of proteolysis, including protein kinase activation, DNA repair and membrane trafficking. Monoubiquitination usually does not lead to proteasomal degradation; instead, it regulates important cellular functions such as chromatin remodeling and vesicle trafficking.

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