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Ubiquitination (Ubiquitylation)

By , BPharm

Ubiquitination, also known as ubiquitylation, is an enzymatic process that involves the bonding of an ubiquitin protein to a substrate protein. This has sometimes been referred to as the molecular “kiss of death” for a protein, as the substrate usually becomes inactivated and is tagged for degradation by the proteasome through the attachment of the ubiquitin molecule.

Post-Translation Modification Enzymes

The process of ubiquitination in regulated by three main types of enzymes to take place in entirety. These include ubiquitin-activating enzymes (E1), ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3). Each of these enzyme types has an important role to play in ubiquitination and the labeling of proteins to be degraded by the proteasome, which are considered in more detail below.

The first step involves the activation of ubiquitin by the E1 enzyme, which occurs prior to its attachment to the amino acid cysteine, the active site. Energy in the form of ATP is required in order for the ubiquitin molecule to be transferred to the active site and produce an intermediate substance known as ubiquitin-adenylate.

Following this, the ubiquitin-conjugating enzyme (E2) plays its role to bring the two molecules together, by transferring the ubiquitin from E1 to the active cysteine site. The E2 enzyme has a particular structure that allows it to bond to both the ubiquitin and E1 molecules and allow this step to occur.

Finally, the ubiquitin protein ligase (E3) is required to recognise and bind the target substrate, subsequently labeling it with the small ubiquitin molecule. This usually occurs by way of an isopeptide bond connecting the last amino acid, glycine 76, of the ubiquitin molecule to a lysine on the substrate protein.

This enzymatic process is then repeated to form a small chain with several ubiquitin molecules, marking the protein for degradation in the proteasome.

Cases of Non-Degradation

Although the labeling of a protein via ubiquitination largely results in the degradation of the protein, there are some cases in which it may not prove fatal.

For example, when a single ubiquitin molecule is bound to a protein without forming a chain of molecules, which is known as mono-ubiquitination, the result can differ significantly. It is common for the protein to instead notice an alteration in function or it may be degraded via lysosomes rather that in the proteasome. This can also occur to some proteins that have undergone poly-ubiquitination, although it is less common.

Additionally, the process of ubiquitination can be reversed through the action of deubiquitinase enzymes, which break the bond between the ubiquitin molecule and the substrate protein.

A Brief History

The theory of ubiquitination involving the labeling of proteins for degradation was discovered in the late 1970s, which led to research about targeting specific cells for degradation.

More recently, breakthrough research furthered the understanding of protein degradation and resulting biological processes, enabling control of cell cycle, gene transcription and immunity. Aaron Ciechanover, Avram Hershko and Irwin Rose received a Nobel Prize for this discovery in 2004.

References

Further Reading

Last Updated: Aug 3, 2015

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