[HTML][HTML] RING finger proteins: mediators of ubiquitin ligase activity

CAP Joazeiro, AM Weissman - Cell, 2000 - cell.com
CAP Joazeiro, AM Weissman
Cell, 2000cell.com
Until recently no specific function had been ascribed to the RING finger beyond a role in
dimerization of several proteins. Over the last year and a half, however, reports from a
number of laboratories studying diverse biological processes have led to the realization that
RING finger proteins play critical roles in mediating the transfer of ubiquitin (Ub) both to
heterologous substrates as well as to the RING finger proteins themselves. As RING fingers
are found in hundreds of proteins, the number of candidate Ub protein ligases (E3s) has …
Until recently no specific function had been ascribed to the RING finger beyond a role in dimerization of several proteins. Over the last year and a half, however, reports from a number of laboratories studying diverse biological processes have led to the realization that RING finger proteins play critical roles in mediating the transfer of ubiquitin (Ub) both to heterologous substrates as well as to the RING finger proteins themselves. As RING fingers are found in hundreds of proteins, the number of candidate Ub protein ligases (E3s) has now increased dramatically.
Protein ubiquitination begins with the formation of a thiol-ester linkage between the C terminus of Ub and the active site cysteine (Cys) of the Ub activating enzyme (E1). Ub is then transferred to an Ub conjugating enzyme (Ubc or E2), again through a thiol-ester linkage. E3s, which are primarily responsible for providing specificity to Ub conjugation, interact with E2 and substrate, facilitating formation of isopeptide bonds between the C terminus of Ub and lysines (Lys) either on a target protein or on the last Ub of a protein-bound multi-Ub chain. Initial models for ubiquitination suggested that E3s facilitate the direct transfer of Ub from E2 to substrate. However, some E3s including E6-associated protein (E6-AP) and other HECT E3s (see below) form thiol-ester intermediates between the conserved HECT Cys and Ub as part of the process leading to the formation of multi-Ub chains on proteins. Multi-Ub chains are potent targeting signals for protein degradation in proteasomes (reviewed in
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