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Allan M. Weissman, M.D.

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Fundamentals of the Ubiquitin System
Fundamentals of the Ubiquitin System
(1) Ubiquitin is synthesized in linear chains or as the N-terminal fusion with small ribosomal subunits that are cleaved by de-ubiquitylating enzymes to form the active protein. Ubiquitin is then activated in an ATP-dependent manner by E1 where a thiol-ester linkage is formed. It is then trans-thiolated to the active site cysteine of an E2. E2s interact with E3s and with substrates and mediate either the indirect (in the case of HECT E3s) or direct transfer of ubiquitin to substrate. A number of factors can affect this process. We know that interactions with Hsp70 can facilitate ubiquitylation in specific instances and competition for lysines on substrates with the processes of acetylation and sumoylation may be inhibitory in certain instances.
(2) For efficient proteasomal targeting to occur, chains of ubiquitin linked internally through K48 must be formed. This appears to involve multiple cycles of E3-mediated transfer of ubiquitin or in some cases other factors known as E4s may play a role in facilitating the processivity of poly-ubiquitin chain formation. Interactions with proteins containing UbDs (ubiquitin domains), including some E3s, may facilitate targeting to the proteasome. For a number of subsrates an ATPase known as p97 (also known as Vcp or in yeast as Cdc48) facilitates transport to proteasomes.
(3) The factors that influence the balance between K48 chains and mono-ubiquitin or other linkages, such as K63 are poorly understood. However, ubiquitin binding domains such as the UBA or UIM could influence this balance in cells by blocking K48 on ubiquitin and thus favoring chain termination or other linkages - this is a point that is far from being established with certainty. Anywhere along the pathway deubiquitylating enzymes may reverse the process, including at the level of the proteasome itself.

This page was last updated on 2/6/2008.