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Ubiquitinylation of cellular proteins is a highly complex and tightly regulated process that targets, in a specific manner, thousands of cellular proteins. It is carried out by a modular cascade of enzymes with high specificity towards target proteins. Conjugation of ubiquitin can serve a variety of non-proteolytic functions, including activation of enzymes, modulation of membrane dynamics, or routing of the tagged proteins to their sub-cellular destination (Figure 1).

Figure 1. Differing ubiquitin modification resulting in distinct functions.


The Ubiquitin Cascade

The attachment of ubiquitin to the ε-amino of lysine residues of target proteins requires a series of ATP-dependent enzymatic steps by ubiquitin activating (E1), ubiquitin conjugating (E2) and ubiquitin ligating (E3) enzymes. Consequently, protein ubiquitinylation is achieved through a minimum of three enzymatic steps. In the first step, in an ATP-dependent process, a ubiquitin-activating enzyme (E1) catalyzes the formation of a reactive thioester bond with ubiquitin. This is followed by its subsequent transfer to the active site cysteine of a ubiquitin carrier protein (E2). The specificity of ubiquitin ligation arises from the subsequent association of the E2-ubiquitin thioester with a substrate-specific ubiquitin:protein isopeptide ligase (E3), which facilitates the formation of the isopeptide linkage between ubiquitin and its target protein. (Figure 2).

Figure 2. Ubiquitin cascade showing activation, conjugation, ligation, deconjugation, and recycling steps.



A small protein of only seventy six amino acids and a molecular weight of ~8.6kDa, ubiquitin (Figure 3) is widely distributed and highly conserved across phylogeny. Ubiquitin contains seven internal lysine residues and terminates with a C-terminal glycyl-glycine motif. It is through this C-terminal glycine residue that ubiquitin attaches itself to the ε-amino group of the side chain of lysine residues within substrate proteins via the formation of an isopeptide bond. In this way, ubiquitin may attach itself as a monomer (mono-ubiquitinylation), as a multiple monomer (multiubiquitinylation), or by internal extension as a polymer (polyubiquitinylation) (Figure 4). The fate of the modified substrate protein will depend upon the exact nature and extent of the modification.

Figure 3: Lysine location within ubiquitin

Figure 4. Types of ubiquitin modification


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