Posttranslational protein modifications by mono- or polyubiquitination are involved in diverse cellular signaling pathways and tightly regulated to ensure proper function of cellular processes. Three types of enzymes, namely ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3), contribute to ubiquitination. Combinations of E2 and E3 enzymes determine ∼ the fate of their substrates via ubiquitination. The seven lysine residues of ubiquitin, Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63, can serve as attachment sites for other ubiquitin molecules. Lys48 (K48)-linked polyubiquitination facilitates recognition of the conjugated protein by proteasome molecules and subsequent proteolytic degradation of the target protein. By contrast, Lys63 (K63)-linked polyubiquitination appears to be involved in polyubiquitin signaling in critical cellular processes, such as DNA repair, regulation of the I-kappaB kinase/NF-kappaB cascade, or T cell receptor signaling, but not protein degradation. In this review, we describe the properties of ubiquitin modification enzymes and the structural interplay among these proteins
