Ubiquitin-conjugating (E2) enzymes are characterized by the presence of a highly conserved ubiquitin-conjugating domain which accommodates ATP-activated ubiquitin (Ub) via a covalently linked thioester onto its active-site residue. E2 enzymes act via selective protein-protein interactions with the ubiquitin-activating E1 enzyme and ubiquitin ligase E3 enzymes and are able to differentiate effects on downstream substrates, either with a single Ub molecule or an Ub chain. While E3s are involved in substrate selection, E2s are the main determinants for selection of the lysine to construct Ub chains, which thereby directly control the cellular fate of the substrate. UbcH3 has been shown to interact with a number of different E3 ligases, including SCFSkp2/Cks1, promoting the ubiquitination of p27 and SCFBTrCP1, promoting the ubiquitination of B-catenin and Ikba.