Ubiquitination

Ubiquitin (Ub), a small protein consisting of 76 amino acids, is found in all tissues of eukaryotic organisms. With only three amino-acid differences between mammals, plants and yeast, Ub displays remarkable evolutionary conservation. The process of tagging a protein with Ub is called ubiquitination and is one of the most versatile known cellular regulatory mechanisms for controlling physiological and pathological cellular events. During the past decade, the functions of Ub have been extended far beyond its role in just directing protein degradation. Now, it is established that ubiquitination is a more important and widespread protein post-translational modification than previously anticipated. Budding of retroviral virions, regulation of transcription factor activity, receptor endocytosis and lysosomal trafficking, control of insulin, and TGF-β signaling pathways are examples of just a few processes that rely on ubiquitination.

Ubiquitination of target proteins is a highly collaborative process between the Ub-activating enzyme (E1), Ub-conjugating enzymes (E2), and Ub ligases (E3). Ub-protein ligases catalyze the process of transfer and covalent attachment of the C-terminus of activated Ub to lysine side chains of the acceptor substrate. The substrate could be mono- or polyubiquitinated, and it was previously believed that canonical K48-linked polyubiquitin chains were the main signal for targeting the substrates for degradation by the 26S proteasome. Nevertheless, it has recently been shown that unconventional polyubiquitin linkages may also target proteins for degradation.

The cellular functions of ubiquitination span a wide spectrum that includes proteolytic and nonproteolytic roles such as proteasomal degradation of proteins; assembly of multiprotein complexes; receptor internalization and downregulation; intracellular trafficking; inflammatory signaling; autophagy; DNA repair and regulation of enzymatic activity. Therefore, deregulation of ubiquitination has broad consequences. It may lead to aberrant activation or deactivation of pathways (such as those involved in cellular metabolism or oncogenesis), improper or insufficient assembly of protein complexes (for instance, during the regulation of inflammatory responses or DNA repair processes), accumulation of misfolded proteins (in the endoplasmic reticulum or in the cytosol during neurodegenerative diseases) or mislocalization of proteins from their functional cellular compartment. Each of these changes can be detrimental to cell functioning. So far, after the approval and successful clinical application of proteasomal inhibitors for the treatment of multiple myeloma, many efforts have been undertaken to target various aspects of the Ub system to treat malignancies as well as metabolic and neurodegenerative diseases.

Figure 1. Ubiquitination and cancer.

With emerging technologies and ever-expanding understanding of ubiquitination processes, these strategies could generate novel therapeutic opportunities for the treatment of human diseases. Creative Biogene is able to offer a variety of ubiquitination related products including stable cell lines, viral particles and clones for your drug discovery projects.

Ubiquitination Product Panel

UBE2A	UBE2E1	UBE2H	UBE2Q1	UBE2O	UBE2G2
UBE2B	UBE2E2	UBE2J1	UBE2W	UBE2D4	UBE2L6
UBE2C	UBE2E3	UBE2J2	UBE2Z	UBE2G1	UBE2D2
UBE2D1	UBE2F	UBE2K

References:

Radivojac P, et al. Identification, Analysis and Prediction of Protein Ubiquitination Sites. Proteins Structure Function & Bioinformatics, 2010, 78(2):365-380.
Shaid S, et al. Ubiquitination and selective autophagy. Cell Death and Differentiation, 2013, 20(1):21-30.
Popovic D, et al. Ubiquitination in disease pathogenesis and treatment. Nature Medicine, 2014, 20(11):1242-1253.

* For research use only. Not intended for any clinical use.

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