Ubiquitin-protein ligases

Open Access
Publisher Website
Google Scholar
Abstract
Doi:10.1242/jcs.01539 Post-translational covalent tagging of proteins with the 76-residue protein ubiquitin (Ub) serves many functions. Polyubiquitylated proteins are directed to the large multi-component, multi-catalytic protease the 26S proteasome. The ubiquitin-26S proteasome (UPS) pathway is the major mechanism by which eukaryotic cells target normal and misfolded cytosolic or membrane proteins for degradation. UPS-mediated degradation of proteins is essential for many cellular processes, including apoptosis, MHC class I antigen presentation, the cell cycle and intracellular signalling. By contrast, mono-ubiquitylation of proteins has non-degradative cellular functions. These include transcriptional activation, methylation of histones, endocytosis and endosomal sorting (Conaway et al., 2002; Sun and Allis, 2002; Raiborg et al., 2003). Protein ubiquitylation is an energy-dependent, four-step pathway that operates in all eukaryotic cell types (Hershko and Ciechanover, 1998; Pickart, 2001). In the first step, which requires ATP, ubiquitin is bound by a thioester linkage through its C-terminal glycine residue to a ubiquitin-activating enzyme (E1). Ubiquitin is then transferred first to one of a number of ubiquitin-conjugating enzymes (E2s) by trans-thiol esterification and then to an e-amino group of a lysine residue in a target protein (T), which is generally facilitated by a ubiquitin-protein ligase (E3). The conjugated ubiquitin itself may then serve as a ubiquitylation substrate and repeated ubiquitylation leads to the formation of a polyubiquitin chain. In general, ubiquitin K48 acts a