Role of ubiquitination

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Role of ubiquitination

The conserved 76-residue polypeptide ubiquitin fulfills essential functions in eukaryotes through its covalent conjugation to other intracellular proteins. Ubiquitin is first activated by an ATP-dependent reaction involving a ubiquitin activating enzyme (E1), followed by its conjugation via a thioester bond to a cysteine residue in a ubiquitin-conjugating enzyme (E2). In the final enzymatic step, ubiquitin is transferred from the E2 enzyme to a target lysine residue in a particular substrate protein by a ubiquitin-protein isopeptide ligase (E3). E3 enzymes are often characterized by the presence of a C3HC4 (RING) finger motif, which binds zinc and is required for ubiquitin ligase activity. Substrates can be mono- or polyubiquitinated; whereas polyubiquitination targets proteins for degradation via the 26S proteasome, monoubiquitination generally acts as a tag that marks the substrate protein to signal for a particular function. One well-characterized example of this process is the monoubiquitination of histones H2A and H2B. The three-step ubiquitination mechanism initiates all known ubiquitination reactions, independent of whether the substrate-bound ubiquitin(s) will signal proteasomal proteolysis, endocytosis, or some other fate.

Because ubiquitination has several possible consequences, the manner in which a covalent ubiquitin signal is interpreted must depend in some cases on additional factors, such as the subcellular localization of the substrate or the number and topology of the substrate-conjugated ubiquitins. For example, substrates destined for proteasomes are usually conjugated to a polyubiquitin chain in which successive ubiquitins are linked by K48-G76 isopeptide bonds, whereas chains linked through K63-G76 bonds have been strongly implicated in nonproteolytic signaling. Nonetheless, specificity in signaling by ubiquitin arises primarily at the stage of ubiquitination. The role of ubiquitin in cell cycle progression, for example, is readily explained by the periodic ubiquitination of positive and negative regulators, leading to the appropriately timed degradation of these factors by proteasomes.

The organization of the enzymatic conjugating cascade is hierarchical: There is one E1; a significant but limited number of E2s, each of which may serve several E3s; and a much larger number of E3s (many which remain to be identified). Each E3 recognizes a set of substrates that share one or more ubiquitination signals, and cooperates with one or a few E2s.

Ubiquitination signals on target proteins can be genetically programmed, or can be acquired by phosphorylation, by binding to an adapter protein, or by protein damage due to fragmentation, oxidation, or aging. The ubiquitin system was first identified as a pathway for the degradation of damaged proteins and that is the other major role it plays. Proteins damaged by oxidation or mutation or that misfold or mislocalize are good substrates for this system. Abnormal proteins in the cytoplasm are bound to the microtubule network and localized to the centrosome along with many of the enzymes of the pathway.22, 23 Misfolded proteins in the ER are shuttled back to the cytoplasm by retrograde transport and ubiquitinated and degraded there.