Themes and variations on ubiquitylation

Abstract

Ubiquitin is a highly conserved 76-amino-acid eukaryotic protein that is covalently attached to proteins as monomers or lysine-linked chains. This review provides an overview of the ubiquitin-conjugating system, highlighting recent insights into the enzymes involved in the addition and removal of ubiquitin from proteins and the consequences of this modification. Ubiquitylation is the result of a highly specific multi-enzyme process, involving classes of enzymes known as E1s, E2s and E3s.There is a single known E1 (ubiquitin-activating enzyme) gene, several E2s (ubiquitin-conjugating enzymes) and a substantially greater number of potential E3s (ubiquitin protein ligases). E2s are characterized by a conserved core domain. Differences among E2s both in the core domain and in amino- and carboxy-terminal extensions have the potential to determine the specificity of E3 interactions and their cellular locations. Specificity in ubiquitylation is conferred primarily by E3s. There are two major classes of E3: HECT domain E3s and RING finger E3s. Crystal structures of members of both classes bound to E2 have now been solved. HECT E3s include E6-AP, implicated in the HPV-E6-dependent degradation of p53, as well as a number of other proteins. Many HECT E3s have a amino-terminal C2 domain and several WW domains. RING finger E3s include single subunit E3s, such as Mdm2 and c-Cbl as well as multisubunit E3s. The latter share the common feature of having a cullin family member as a component of the active complex. Ubiquitylation is reversible. Removal of ubiquitin from proteins, disassembly of multi-ubiquitin chains, and processing of ubiquitin precursors to mature forms are among the jobs carried out by de-ubiquitylating enzymes. Modification with ubiquitin is classically associated with protein degradation by targeting to proteasomes. However, ubiquitin has other cellular roles not obviously associated with proteasomal degradation and it is also evident that the types of ubiquitin linkages formed may influence protein fate.