Ubiquitin Enzymes & DUBs
Ubiquitination (ubiquitinylation) is a post-translational modification (PTM) process, where a ubiquitin is added to a lysine/cysteine/ serine/threonine of a substrate protein via the C-terminal glycine of ubiquitin. It is essential for balancing numerous physiological processes. Through altering proteins' degradation, cellular location, activity, and interactions with other molecules, ubiquitination regulates protein functions in relevant signaling pathways.
The small ubiquitin protein, made up of 76 amino acids (about 8.6 kDa), can be found ubiquitously in most tissues of eukaryotic organisms. As ubiquitination happens to proteins in a wide range of signaling pathways, it has been implicated in the pathogenesis of a variety of diseases and disorders such as neurodegenerative diseases, infection and immunity related diseases and cancers.
CD BioSciences offers a complete portfolio of solutions to study protein ubiquitination including ubiquitination profiling, E3s/DUBs identification, substrate identification, and inhibitor/activator screening.
Ubiquitin Enzymes and Ubiquitination
Ubiquitination consists of three steps and is catalyzed by different sets of enzymes.
Ubiquitin is activated by ubiquitin-activating enzymes (E1s). There are only two E1s in humans, i.e., UBA1 and UBA6.
Ubiquitin is transferred by ubiquitin-conjugating enzymes (E2s). Humans possess 35 different E2s, structurally characterized by the highly conserved ubiquitin-conjugating catalytic (UBC) fold.
Ubiquitin is added to substrate proteins by ubiquitin ligases (E3s), which are capable of interacting with E2s and recognizing substrate proteins. Presumably, over 600 E3 ligases are encoded by the human genome, allowing for a highly diverse set of substrates.
DUBs and Deubiquitination
Deubiquitinating enzymes (DUBs) remove ubiquitin from substrate proteins. Just like E3s, the DUBs also possess specificity with substrates. There are nearly 102 putative DUB genes in humans genome.
Types of Ubiquitination
- Monoubiquitination is the ligation of a single ubiquitin molecule to one substrate protein residue. When monoubiquitination happens to several residues, it is termed multi-monoubiquitination. Monoubiquitination regulates cellular processes such as DNA repair, membrane trafficking, endocytosis and viral budding.
- Polyubiquitination is the formation of ubiquitin chain on a single residue, usually lysine, on the substrate protein. Following the ligation of the first ubiquitin, more ubiquitin proteins are added to the first one on lysine (K6, K11, K27, K29, K33, K48, K63) or N-terminus.
|Introduction of K48 and K63 Polyubiquitination
|The best-characterized Lysine 48-linked (K48) polyubiquitin chains, target proteins for proteasomal degradation, which is known as the proteolysis process. After rapid degradation of proteins, ubiquitin molecules are recycled for further use.
|Lysine 63-linked (K63) polyubiquitination fulfills a proteasome-independent role, which coordinates cellular processes such as endocytic trafficking, inflammation, translation, and DNA repair. Together with other lysine chains, it requires more study.
SUMOylation is also a reversible PTM, where a Small Ubiquitin-like Modifier (SUMO) protein is covalently conjugated to a lysine residue in a target protein to modify its function. The enzymatic cascade of SUMOylation is analogous to, but distinct from, ubiquitination.
In general, SUMOylation shares similar research approaches with ubiquitination.
Solutions for Ubiquitin Enzymes & DUBs
- Profiling global protein ubiquitination in a biological system (cells, tissues, etc).
- Detecting ubiquitination of proteins in specific signaling pathways.
- Comparing Ubiquitination levels in different conditions.
- Identifying substrate proteins for E3s/DUBs.
- Determining the ubiquitin sites on substrates.
- Analyzing the types of ubiquitination. (Whether it is proteasome-dependent.)
- Identifying E3s/DUBs for your substrates and E2s related to the E3.
- Determining function domain or catalytic site on E2s/E3s/DUBs.
- Analyzing the structures of E2s/E3s/DUBs.
- Screening for inhibitors/activators for E2s/E3s/DUBs.
- Determining the thermodynamic parameters of the interactions.
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For research use only. Not intended for any clinical use.