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Ubiquitin and Ubiquitin-like Proteins (Ubls)

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.

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.

Figure 3: Lysine location within ubiquitin



Figure 4. Types of ubiquitin 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)
 

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