Getting into position: the catalytic mechanisms of protein ubiquitylation

Abstract

The role of protein ubiquitylation in the control of diverse cellular pathways has recently gained widespread attention. Ubiquitylation not only directs the targeted destruction of tagged proteins by the 26 S proteasome, but it also modulates protein activities, protein-protein interactions and subcellular localization. An understanding of the components involved in protein ubiquitylation (E1s, E2s and E3s) is essential to understand how specificity and regulation are conferred upon these pathways. Much of what we know about the catalytic mechanisms of protein ubiquitylation comes from structural studies of the proteins involved in this process. Indeed, structures of ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) have provided insight into their mechanistic details. E3s (ubiquitin ligases) contain most of the substrate specificity and regulatory elements required for protein ubiquitylation. Although several E3 structures are available, the specific mechanistic role of E3s is still unclear. This review will discuss the different types of ubiquitin signals and how they are generated. Recent advances in the field of protein ubiquitylation will be examined, including the mechanisms of E1, E2 and E3. In particular, we discuss the complexity of molecular recognition required to impose selectivity on substrate selection and topology of poly-ubiquitin chains.

Up-Regulation of Genes Related to the Ubiquitin-Proteasome System in the Brown Adipose Tissue of 24-h-Fasted Rats

“…Moreover, we found that the genes related to E3 ubiquitin ligase were up-regulated in BAT of the fasted rats (Table 5). E3 ubiquitin ligase is considered to determine the substrate specificity for protein ubiquitination, 28,29) and the result suggests that there are potential target proteins for ubiquitination other than ACC.…”

Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment

“…The ligase specifically recognizes the substrate protein and transfers ubiquitin to the target protein. 18 Subsequently, the target proteins are unfolded and degraded by an ATP-dependent process. 19 Two muscle-specific E3 ubiquitin ligases named muscle atrophy Fbox (MAFbx, atrogin-1) and muscle RING finger-1 (MuRF-1) were first described in 2001 and are significantly up-regulated during muscle atrophy.…”

Mechanistic insight into the allosteric activation of a ubiquitin-conjugating enzyme by RING-type ubiquitin ligases

“…Ubiquitin is then transferred to ubiquitin-conjugating enzymes (E2s) as a thioester. Ubiquitin ligases (E3s) facilitate the attachment of ubiquitin to -amino groups of lysines and, rarely, to the N-terminal amino group in substrates (1,(3)(4)(5)(6). HECT (homology to E6AP C terminus) domain-containing E3s form intermediate thioesters with ubiquitin at their active-site cysteines before transferring the ubiquitin to substrates (3,4,7).…”

“…Ubiquitination is catalyzed by a cascade of enzymes (1,3,4). The active-site cysteine of ubiquitin-activating enzyme (E1) forms a thioester with ubiquitin in an ATP-dependent reaction.…”