Ubiquitin Proteasome Pathway

Ubiquitin is a 76-amino acid protein which is found in every cell in the body. The ubiquitin system controls protein turnover by regulating the turnover of proteins involved in a broad range of regulatory pathways, including DNA damage and repair, cell cycle progression, apoptosis, receptor-mediated endocytosis and signal transduction.

Ubiquitination is when one or more ubiquitins are added to a protein or peptide. Ubiquitination also has the added effect of tagging the target protein for degradation by either proteasomes or lysosomes. There are three main types of ubiquitination and they are called are called "monoubiquitination," "polyubiquitination" and "multisite mono-ubiquitination". Monoubiquitinated proteins are only attached once with one single ubiquitin molecule. Polyubiquitinated proteins are when multiple ubiquitin molecules are attached to a single protein. Multisite mono-ubiquitinated proteins are when more than one ubiquitin molecule is attached to a single lysine residue of a target protein.

Assay Genie has a range of ubiquitin ligases. Ubiquitin chains can be formed by any one of three different ligase enzymes; ubiquitin-activating enzyme (E1), the ubiquitin-conjugating enzyme (E2) and the ubiquitinating enzyme (E3). UBR1 is an E3 ubiquitin ligase which is known for its ability to target protein degradation by the N-end rule.

Deubiquitinases (DUBs) are deubiquitinating enzymes that remove ubiquitin, a small protein ligand attached to proteins to mark them for degradation. DUBs are categorized into three groups: ubiquitin carboxyl-terminal hydrolases (UCHs), ubiquitin specific proteases (USPs) and JAB1/MPN domain-containing hydrolases. UCHs deubiquitinate proteins by hydrolyzing the ubiquitin from a protein substrate. USPs deubiquitylate substrates with an amino acid motif called the deubiquitylation target sequence (DTS). The third class, JAB1/MPN domain-containing deubiquitinating enzymes, deubiquitylate target proteins with a conserved 'Lys-Thr' motif called the deubiquitylation signature (Ubl).

In mammal cells, ubiquitin is covalently attached to lysine residues on target proteins by an isopeptide bond through its C-terminal glycine residue. The active deubiquitinating enzyme removes the ubiquitin moieties from target proteins in order to halt protein degradation. DUBs are therefore linked to cellular regulation, DNA damage repair and even cancer progression.

DUBs have been implicated with tumorigenesis by deubiquitinating tumor suppressor proteins (TSPS) to promote cell proliferation and deubiquitinating oncoproteins such as p53 to deactivate tumor suppressor activity. DUBs may also deubiquitinate proteins other than TSPS and thus facilitate tumorigenesis indirectly by deactivating the deubiquitinating machinery.