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Ubiquitin and Ubiquitin-like Proteins (Ubls)
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Ubiquitin & Ubl Signaling Catalog
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).
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).
About Ubiquitin
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.
Ubiquitin-like Proteins
There are at least 10 conjugatable ‘cousins’ of ubiquitin including, amongst others, SUMO, NEDD8, ISG15 and FAT10. These ubiquitin-like proteins (Ubls) can be covalently attached to target proteins for a variety of signalling processes in the cell and may function as critical regulators of many cellular processes, including transcription, DNA repair, signal transduction, autophagy, and cell-cycle control. There is a growing body of data implicating the dysregulation of Ubl-substrate modification and mutations in the Ubl-conjugation machinery in the etiology and progression of a number of human diseases.
Literature References
- The complete amino acid sequence of ubiquitin, an adenylate cyclase stimulating polypeptide probably universal in living cells: D.H. Schlesinger, et al.; Biochemistry 14, 2214 (1975)
- Ubiquitin superfolds: intrinsic and attachable regulators of cellular activities?: R.J. Mayer, et al.; Fold. Des. 3, R97 (1998)
- Ubiquitin and ubiquitin-like proteins as multifunctional signals: R.L. Welchman, et al.; Nat. Rev. Mol. Cell Biol. 6, 599 (2005)
- Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry: D. Meierhofer, et al.; J. Proteome Res. 7, 4566 (2008)
- Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages: H.T. Kim, et al.; J. Biol. Chem. 282, 17375 (2007)
- A ubiquitin ligase complex assembles linear polyubiquitin chains: T. Kirisako, et al.; EMBO J. 25, 4877 (2006)
- Ubiquitylation on canonical and non-canonical sites targets the transcription factor neurogenin for ubiquitin-mediated proteolysis: J.M. Vosper, et al.; J. Biol. Chem. 284, 15458 (2009)
- The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction: M.H. Glickman & A. Ciechanover; Physiol. Rev. 82, 373 (2002)
- Modification of proteins by ubiquitin and ubiquitin-like proteins:O. Kerscher, et al.; Annu. Rev. Cell Dev. Biol. 22, 159 (2006)
- Innate link between NF-kappaB activity and ubiquitin-like modifiers: V. Lang and M.S. Rodriguez; Biochem. Soc. Trans. 36, 853 (2008)
- A role for ubiquitin in selective autophagy: V. Kirkin, et al.; Mol. Cell 34, 259 (2009)
- Mechanism and function of deubiquitinating enzymes: A.Y. Amerik & M. Hochstrasser; Biochim. Biophys. Acta 1695, 189 (2004)
