E3 Ubiquitin Ligases

E3 Ubiquitin Ligases Background

About E3 Ubiquitin Ligases

Almost all intracellular proteins and some extracellular proteins are constantly renewed through degradation and replacement by newly synthesized proteins. Protein degradation occurs through two major pathways: autophagy and the ubiquitin-proteasome system (UPS), both of which are essential for the maintenance of cellular homeostasis. The UPS is a cascade of reactions that are important for the degradation of short-lived, misfolded, and damaged proteins. The UPS has been reported to regulate the degradation of more than 80% of proteins in the cell, and its dysregulation has been found in most cancer features. Most importantly, E3 ligase is an essential component of the UPS that provides regulatory specificity. E3 ubiquitin ligase regulates the final step of the enzyme cascade, which also consists of ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzyme (E2). The E3 ligase selectively attaches ubiquitin to lysine, serine, threonine, or cysteine residues of a specific substrate. The process of attaching ubiquitin and ubiquitin-like proteins (Ubl) to cellular proteins is known as ubiquitination, and it plays a crucial role in the post-translational modification (PTM) process. The ubiquitin-proteasome degradation pathway has been reported to be one of the most important mechanisms controlling protein expression levels.

Ubiquitination is one of the important post-translational modifications of proteins in vivo and signals protein degradation. Ubiquitin ligase E3 is one of the key enzymes in the ubiquitination process, mediating the transfer of activated ubiquitin from conjugating enzyme E2 to the substrate. Different ubiquitin ligases act on different substrate proteins, determining the specificity of ubiquitination modifications. A large number of E3 ligases, but only a small number of E1 and E2 ligases, will be present in different organisms. Based on their structure and function, E3 ligases can be broadly categorized into four types: HECT-type, U-box-type, RING-finger-type, and RBR-type. Interestingly, different types of E3 ligases have low sequence homology and large compositional differences.

Types of ubiquitination ligasesFig. 1. Types of ubiquitination ligases. (Yang Q, et al., 2021)

Mechanism of E3 Ubiquitin Ligases

The action of E3 ubiquitin ligases involves a multi-step process that begins with the recognition of a specific substrate. E3 ligases have specific binding domains that allow them to interact with target proteins in a highly selective manner. Once the substrate is recognized, the E3 ligase facilitates the transfer of ubiquitin from the E2 splicing enzyme to the target protein either directly (in the case of HECT ligases) or indirectly (in the case of RING ligases). This covalent attachment of the ubiquitin molecule occurs through the formation of an isopeptide bond between a glycine residue at the C-terminus of ubiquitin and a lysine residue on the substrate protein.

Relevance of E3 Ubiquitin Ligases to Disease

E3 ubiquitin ligases regulate homeostasis, cell cycle, and DNA repair pathways, and as a result, a number of these proteins are involved in a variety of cancers, including famously MDM2, BRCA1, and Von Hippel-Lindau tumor suppressor. For example, a mutation of MDM2 has been found in stomach cancer, renal cell carcinoma, and liver cancer (amongst others) to deregulate MDM2 concentrations by increasing its promoter’s affinity for the Sp1 transcription factor, causing increased transcription of MDM2 mRNA. Several proteomics-based experimental techniques are available for identifying E3 ubiquitin ligase-substrate pairs, such as proximity-dependent biotin identification (BioID), ubiquitin ligase-substrate trapping, and tandem ubiquitin-binding entities (TUBEs).

Multi-functions of E3 ligasesFig. 2. Multi-functions of E3 ligases. (Yang Q, et al., 2021)

Available Resources of E3 Ubiquitin Ligases

Creative BioMart is a leading supplier of high-quality products and services, offering a comprehensive line of E3 ligase products, including recombinant proteins, cell & tissue lysates, protein pre-coupled magnetic beads, and other products to support relevant research. Such as the role of E3 ligases in protein regulation and cellular processes, E3 ligase-substrate interactions, ubiquitin transfer assays, and the identification of novel E3 ligase inhibitors or activators. We offer the following E3 ubiquitin ligases-related products to our customers:

In addition to products and customization services, Creative BioMart offers E3 ubiquitin ligases - related signaling pathways, protein functions, interactions proteins, research areas, and other resources to support the study of various biological processes and pathways.

E3 ubiquitin ligase is an important component of UPS and plays a key role in protein degradation and cell regulation. Creative BioMart provides researchers with a wide range of resources and tools to advance our understanding of E3 ligase biology and its impact on a variety of biological processes and diseases. With its high-quality products, researchers can explore the function, regulation, and therapeutic potential of E3 ubiquitin ligases in research. Please note that product types and resources vary for each E3 ubiquitin ligase, the information on this page is for reference only, please contact us with any questions or requests.


  1. Yang Q, Zhao J, Chen D, Wang Y. E3 ubiquitin ligases: styles, structures and functions. Mol Biomed. 2021 Jul 30;2(1):23.
  2. Ardley HC, Robinson PA. E3 ubiquitin ligases. Essays Biochem. 2005;41:15-30. doi: 10.1042/EB0410015. PMID: 16250895.


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